Disease Information

General Information of the Disease (ID: DIS00080)

• Name: Melanoma
• ICD: ICD-11: 2C30

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 16 drug(s) in total

Binimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Drug: Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; .
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Drug: Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; .
• Mechanism Description: The missense mutation p.V600X (c.1798_1800) in gene BRAF cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; .
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Sensitive Drug: Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; .
• Mechanism Description: The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61R (c.182A>G)
• Sensitive Drug: Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; .
• Mechanism Description: The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Drug: Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; .
• Mechanism Description: The missense mutation p.Q61L (c.182A>T) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61R (c.182A>G)
• Sensitive Drug: Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; .
• Mechanism Description: The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Drug: Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; .
• Mechanism Description: The missense mutation p.Q61L (c.182A>T) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-301 [3]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/FAKT signaling pathway; Activation; hsa04151
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SkMEL1 cells; Skin; Homo sapiens (Human); CVCL_0068
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
• Mechanism Description: PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.

Key Molecule: hsa-mir-211 [4]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Methylation; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpressed 211 could enhance the anticancer effect of cisplatin and restoration of miR-211 rendered susceptibility to cisplatin in cisplatin-resistant cells.miR-211 could be transcriptionally repressed by EZH2 mediated promoter methylation.

Key Molecule: hsa-miR-30a-5p [5]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/P53 signaling pathway; Regulation; hsa04151
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: M8 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: Sk-Mel-19 cells; Skin; Homo sapiens (Human); CVCL_6025
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-30a-5p was over-expressed in cisplatin resistant melanoma cells and could influence the activity of PI3k/AkT and the protein level of P53 by targeting IGF1R gene.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [3]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/FAKT signaling pathway; Activation; hsa04151
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SkMEL1 cells; Skin; Homo sapiens (Human); CVCL_0068
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
• Mechanism Description: PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [4]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpressed 211 could enhance the anticancer effect of cisplatin and restoration of miR-211 rendered susceptibility to cisplatin in cisplatin-resistant cells.miR-211 could be transcriptionally repressed by EZH2 mediated promoter methylation.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [5]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/P53 signaling pathway; Regulation; hsa04151
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: M8 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: Sk-Mel-19 cells; Skin; Homo sapiens (Human); CVCL_6025
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-30a-5p was over-expressed in cisplatin resistant melanoma cells and could influence the activity of PI3k/AkT and the protein level of P53 by targeting IGF1R gene.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-488-3p [6]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: B16 cells; Skin; Homo sapiens (Human); CVCL_F936
• In Vitro Model: HEMn-LP cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM451 cells; Skin; Homo sapiens (Human); CVCL_6357
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: microRNA-488-3p sensitizes malignant melanoma cells to cisplatin by targeting PRkDC.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA-dependent catalytic protein kinase (PRKDC) [6]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: B16 cells; Skin; Homo sapiens (Human); CVCL_F936
• In Vitro Model: HEMn-LP cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM451 cells; Skin; Homo sapiens (Human); CVCL_6357
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: microRNA-488-3p sensitizes malignant melanoma cells to cisplatin by targeting PRkDC.

Dabrafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-miR-126-3p [7]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.

Key Molecule: Vascular endothelial growth factor A (VEGFA) [7]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myeloma cell metalloproteinase (ADAM9) [7]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.

Key Molecule: GTPase KRas (KRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61H
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.

Key Molecule: GTPase KRas (KRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12R
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.

Key Molecule: GTPase KRas (KRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12C
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.

Key Molecule: GTPase Nras (NRAS) [8], [9], [10]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Sanger sequencing assay; Next generation assay; Single PCR-based analysis
• Experiment for Drug Resistance: Progression-free and post-progression survival asaay; Computed tomography assay; Positron emission tomography assay
• Mechanism Description: Another post-relapse tumor harbored an acquired NRASQ61k missense mutation together with focal BRAF amplification. The resistant tumor from a third patient harbored both a MEk2 mutation and BRAF amplification. Resistance mechanisms are identified in 9/11 progressing tumours and MAPk reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEk2. Our data confirming that MEk2C125S, but not the synonymous MEk1C121S protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEk2 mutations in combination therapy-resistant melanomas.

Key Molecule: GTPase Nras (NRAS) [8], [11]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61R
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next generation assay; Single PCR-based analysis
• Experiment for Drug Resistance: Computed tomography assay; Positron emission tomography assay; Progression-free and overall survival assay
• Mechanism Description: NRAS mutations (Q61R and Q61k in codon 61) were detected in two of ten patients (20%). Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: MAPK/ERK kinase 2 (MEK2) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.N126D
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.

Key Molecule: MAPK/ERK kinase 2 (MEK2) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L46F
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.

Key Molecule: MAPK/ERK kinase 2 (MEK2) [12]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.C125S
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: One portion of the tumour screened by capillary sequencing of reverse transcription PCR (RT-PCR) products contained both the MEk1G128D and MEk2C125S mutations and demonstrated MAPk reactivation.

Key Molecule: MAPK/ERK kinase 2 (MEK2) [13]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q60P
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Recent whole-exome and RNA sequencing studies have identified a wide array of acquired mutations that confer resistance, including those that reactivate the MAPk pathway (NRAS, kRAS, and MEk1/2 mutations, NF1 loss, BRAF amplification, and BRAF splice variants) and those that activate the PI3k pathway (PIk3CA, PIk3R1, and AkT1/2 mutations and PTEN loss). Of the 6 samples with putative resistance-conferring alterations, 15C harbored an acquired missense PTENR159S mutation in the phosphatase domain, 25C harbored a known acquired MEkQ60L mutation.

Key Molecule: GTPase Nras (NRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G13R
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12R
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [8], [12]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12D
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy. The Prog that did not show evidence of MAPk reactivation by GSEA had two identified resistance mechanisms (MEk2E207k and NRASG12D), but both variants occurred at low frequency (13 and 15% allelic frequency, respectively, by whole-exome sequencing), suggesting heterogeneity within the Prog metastasis.

Key Molecule: MAPK/ERK kinase 2 (MEK2) [12]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.E207K
• Resistant Drug: Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: The Prog that did not show evidence of MAPk reactivation by GSEA had two identified resistance mechanisms (MEk2E207k and NRASG12D), but both variants occurred at low frequency (13 and 15% allelic frequency, respectively, by whole-exome sequencing), suggesting heterogeneity within the Prog metastasis.

Dabrafenib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [16]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [17]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Dacarbazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-31 [18]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Dacarbazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HT144 cells; Skin; Homo sapiens (Human); CVCL_0318
• In Vitro Model: SkMEL5 cells; Skin; Homo sapiens (Human); CVCL_0527
• In Vitro Model: SkMEL1 cells; Skin; Homo sapiens (Human); CVCL_0068
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A875 cells; Skin; Homo sapiens (Human); CVCL_4733
• In Vitro Model: M21 cells; Skin; Homo sapiens (Human); CVCL_D031
• In Vitro Model: SkMEL13 cells; Skin; Homo sapiens (Human); CVCL_6022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-31 could suppress tumor growth and enhance sensitivity to dacarbazine (DTIC) by down-regulating SOX10 mainly via inhibiting PI3k/AkT signaling pathway in melanoma.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor SOX-10 (SOX10) [18]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Dacarbazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HT144 cells; Skin; Homo sapiens (Human); CVCL_0318
• In Vitro Model: SkMEL5 cells; Skin; Homo sapiens (Human); CVCL_0527
• In Vitro Model: SkMEL1 cells; Skin; Homo sapiens (Human); CVCL_0068
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A875 cells; Skin; Homo sapiens (Human); CVCL_4733
• In Vitro Model: M21 cells; Skin; Homo sapiens (Human); CVCL_D031
• In Vitro Model: SkMEL13 cells; Skin; Homo sapiens (Human); CVCL_6022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-31 could suppress tumor growth and enhance sensitivity to dacarbazine (DTIC) by down-regulating SOX10 mainly via inhibiting PI3k/AkT signaling pathway in melanoma.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-301 [3]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/FAKT signaling pathway; Activation; hsa04151
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SkMEL1 cells; Skin; Homo sapiens (Human); CVCL_0068
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
• Mechanism Description: PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.

Key Molecule: hsa-mir-424 [19]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: PARP cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [3]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/FAKT signaling pathway; Activation; hsa04151
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SkMEL1 cells; Skin; Homo sapiens (Human); CVCL_0068
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
• Mechanism Description: PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.

Key Molecule: Programmed cell death protein 4 (PDCD4) [19]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: PARP cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-424 [19]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: PARP cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Programmed cell death protein 4 (PDCD4) [19]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: PARP cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.

Nivolumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [20]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Resistant Drug: Nivolumab
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [20]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Drug: Nivolumab
• Experimental Note: Identified from the Human Clinical Data

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-326 [21]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Histone deacetylase 3 (HDAC3) [21]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-335 [21], [22]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR335/SIAH2/HDAC3 signaling pathway; Regulation; hsa05206
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Trypan blue exclusion assay; Transwell assay
• Mechanism Description: miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

Key Molecule: hsa-mir-217 [21]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-200b [21]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

Key Molecule: hsa-miR-326 [21]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: E3 ubiquitin-protein ligase SIAH2 (SIAH2) [22]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR335/SIAH2/HDAC3 signaling pathway; Regulation; hsa05206
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue exclusion assay; Transwell assay
• Mechanism Description: miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

Palbociclib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cyclin-dependent kinase 4 (CDK4) [23]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.R24C (c.70C>T)
• Sensitive Drug: Palbociclib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; .
• Experiment for Molecule Alteration: Western blotting analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: SRB assay

Pembrolizumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [24]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61R
• Resistant Drug: Pembrolizumab
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Circulating tumour DNA (ctDNA) analysis; Whole genome plasma DNA sequencing assay
• Experiment for Drug Resistance: Computer tomography (CT) assay; Positron emission tomography assay
• Mechanism Description: Mutations in NRAS have been found in 8-26% of patients with acquired resistance to BRAF inhibitors. We analysed the presence of NRASQ61k and NRASQ61R in the ctDNA extracted from 7 melanoma patients with progressive disease who had previously responded to treatment with vemurafenib (n = 2) or dabrafenib/trametinib (n = 5). Two samples were positive for NRASQ61k and one sample had an NRASQ61R mutation, all three were derived from patients treated with dabrafenib/trametinib.

Temozolomide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-203 [25]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT144 cells; Skin; Homo sapiens (Human); CVCL_0318
• In Vitro Model: SkMEL5 cells; Skin; Homo sapiens (Human); CVCL_0527
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR203 sensitizes MM cells to TMZ by targeting GLS.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: L-glutamine amidohydrolase (GLS) [25]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT144 cells; Skin; Homo sapiens (Human); CVCL_0318
• In Vitro Model: SkMEL5 cells; Skin; Homo sapiens (Human); CVCL_0527
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis; Immunohistochemistry assays
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR203 sensitizes MM cells to TMZ by targeting GLS.

Trametinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V60E (c.179T>A)
• Resistant Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [26]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.D594G (c.1781A>G)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: HTB-56 cells; Pleural effusion; Homo sapiens (Human); CVCL_0236
• In Vitro Model: HTB-38 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HTB-183 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H661 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H508 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5944 cells; Ascites; Homo sapiens (Human); CVCL_1551
• In Vitro Model: CRL-5885 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: CRL-5883 cells; Pleural effusion; Homo sapiens (Human); CVCL_1483
• In Vitro Model: CRL-5868 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5803 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: CCL-253 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: CCL-185 cells; Bowel; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [27]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597Q (c.1790T>A)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [28]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K601E (c.1801A>G)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.K601E (c.1801A>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [29]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K601E (c.1801A>G)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [29]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597R (c.1790T>G)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-gene resequencing assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [29]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600R (c.1798_1799delGTinsAG)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [30]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597V (c.1789C>G)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Molecule Alteration: Tumour genotyping assay
• Mechanism Description: The missense mutation p.L597V (c.1789C>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [28]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; .
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [31]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.D594V (c.1781A>T)
• Sensitive Drug: Trametinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.D594V (c.1781A>T) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [32]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Synonymous; p.K601K (c.1803A>G)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Synonymous; p.L597L (c.1791A>T)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [29]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K601R (c.1802A>G)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [30]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597R (c.1790T>G)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293H cells; Fetal kidney; Homo sapiens (Human); CVCL_ZK99
• Experiment for Molecule Alteration: Whole genome sequencing assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data

Trametinib/Dabrafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [33]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Sensitive Drug: Trametinib/Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Drug Resistance: Tumor evaluation assay

Tryptophan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [34]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tryptophan
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Activation; hsa04010
• In Vivo Model: VillinCreErt2 and VillinCreErt2 APCfl/fl KRASG12D/+ C57BL/6J mouse model; Mus musculus
• Experiment for Molecule Alteration: Amino acid mass spectrometry assay
• Experiment for Drug Resistance: Flow cytometry (SIINFEKL assays); T cell killing assay and clonogenic assay
• Mechanism Description: Sloppiness is defined by ribosomal frameshifting upon tryptophan shortage. MAPK pathway hyperactivation links sloppiness to cancer. Drug-resistant cancer cells remain sloppy and are targeted by T cells.

Key Molecule: Ras-specific guanine nucleotide-releasing factor 2 (RGRF2) [34]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tryptophan
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Activation; hsa04010
• In Vivo Model: VillinCreErt2 and VillinCreErt2 APCfl/fl KRASG12D/+ C57BL/6J mouse model; Mus musculus
• Experiment for Molecule Alteration: Amino acid mass spectrometry assay
• Experiment for Drug Resistance: Flow cytometry (SIINFEKL assays); T cell killing assay and clonogenic assay
• Mechanism Description: Sloppiness is defined by ribosomal frameshifting upon tryptophan shortage. MAPK pathway hyperactivation links sloppiness to cancer. Drug-resistant cancer cells remain sloppy and are targeted by T cells.

Vemurafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [35]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Structural variation; Copy number gain
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall or disease-free survival assay
• Mechanism Description: Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-204-5p [36]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ERK1/2/MEK activation signaling pathway|hsa04210); Regulation
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: PI3K signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR204-5p and miR211-5p contribute to BRAF inhibitor resistance in melanoma. MTT assays revealed a moderate but consistent increase in resistance to VMF in cells overexpressing miR211-5p or miR204-5p. Joint overexpression of miR204-5p and miR211-5p durably stimulated Ras and MAPk upregulation. Resistance to BRAFi in melanoma involves genetic alterations that lead to reactivation of the MAPk pathway or activation of PI3-k/AkT signalling.

Key Molecule: hsa-miR-211-5p [36]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ERK1/2/MEK activation signaling pathway|hsa04210); Regulation
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: PI3K signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR204-5p and miR211-5p contribute to BRAF inhibitor resistance in melanoma. MTT assays revealed a moderate but consistent increase in resistance to VMF in cells overexpressing miR211-5p or miR204-5p. Joint overexpression of miR204-5p and miR211-5p durably stimulated Ras and MAPk upregulation. Resistance to BRAFi in melanoma involves genetic alterations that lead to reactivation of the MAPk pathway or activation of PI3-k/AkT signalling.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [36]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ERK1/2/MEK activation signaling pathway|hsa04210); Regulation
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: PI3K signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blotting analysis; GTPase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR204-5p and miR211-5p contribute to BRAF inhibitor resistance in melanoma. MTT assays revealed a moderate but consistent increase in resistance to VMF in cells overexpressing miR211-5p or miR204-5p. Joint overexpression of miR204-5p and miR211-5p durably stimulated Ras and MAPk upregulation. Resistance to BRAFi in melanoma involves genetic alterations that lead to reactivation of the MAPk pathway or activation of PI3-k/AkT signalling.

Key Molecule: GTPase KRas (KRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61H
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.

Key Molecule: GTPase KRas (KRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12R
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.

Key Molecule: GTPase KRas (KRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12C
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.

Key Molecule: GTPase Nras (NRAS) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61H
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: In contrast, NRAS mutations and BRAF amplifications may still prove responsive to subsequent MEk inhibitor-based regimens, although the existing clinical data suggests that patients who progress following single-agent RAF inhibition are less likely to benefit from MEk inhibitors.

Key Molecule: MAPK/ERK kinase 2 (MEK2) [10]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.F57C
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Capillary sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required. Functional analyses confirmed that MEk1k57E and MEk2F57C mutants restored extracellular signal-regulated kinase (ERk) activation in the presence of dabrafenib, whereas MEk1G176S did not alter melanoma cell sensitivity to dabrafenib.

Key Molecule: MAPK/ERK kinase 2 (MEK2) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V35M
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.

Key Molecule: MAPK/ERK kinase 2 (MEK2) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.C125S
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.

Key Molecule: PI3-kinase alpha (PIK3CA) [37]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.E545K
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: In patient #11, sequential biopsies showed three mutations that were not detected in the pretreatment biopsy, including an activating mutation in PIk3CA E545k readily explaining the resistance.

Key Molecule: Phosphatase and tensin homolog (PTEN) [13]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.R159S
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Activation; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Recent whole-exome and RNA sequencing studies have identified a wide array of acquired mutations that confer resistance, including those that reactivate the MAPk pathway (NRAS, kRAS, and MEk1/2 mutations, NF1 loss, BRAF amplification, and BRAF splice variants) and those that activate the PI3k pathway (PIk3CA, PIk3R1, and AkT1/2 mutations and PTEN loss). Of the 6 samples with putative resistance-conferring alterations, 15C harbored an acquired missense PTENR159S mutation in the phosphatase domain, 25C harbored a known acquired MEkQ60L mutation.

Key Molecule: GTPase Nras (NRAS) [8], [9], [38]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61R
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vitro Model: M229 cells; Skin; Homo sapiens (Human); CVCL_D748
• In Vitro Model: M238 cells; Skin; Homo sapiens (Human); CVCL_D751
• In Vitro Model: M249 cells; Skin; Homo sapiens (Human); CVCL_D755
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [8], [9], [38]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• In Vitro Model: M229 cells; Skin; Homo sapiens (Human); CVCL_D748
• In Vitro Model: M238 cells; Skin; Homo sapiens (Human); CVCL_D751
• In Vitro Model: M249 cells; Skin; Homo sapiens (Human); CVCL_D755
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G13R
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12R
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [8]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12D
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/PTEN signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free and overall survival assay
• Mechanism Description: Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.

Key Molecule: GTPase Nras (NRAS) [39], [35]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Liquid biopsy assay; Next-generation sequencing assay; Circulating-free DNA assay; Digital PCR assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Overexpression of PDGFRbeta or N-RAS(Q61k) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines.

Key Molecule: GTPase Nras (NRAS) [40]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Mechanism Description: BRAFV600E inhibition via vemurafenib induces paradoxical activation of MAPK through increased CRAF activity and acquired NRAS mutation. Moreover, mutations in genes upstream of RAF, such as the activating N-RASQ61K mutation, allow for BRAFV600 melanomas to escape molecular targeting.

Key Molecule: GTPase Nras (NRAS) [40]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Mechanism Description: BRAFV600E inhibition via vemurafenib induces paradoxical activation of MAPK through increased CRAF activity and acquired NRAS mutation. Moreover, mutations in genes upstream of RAF, such as the activating N-RASQ61K mutation, allow for BRAFV600 melanomas to escape molecular targeting.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Autophagy protein 5 (ATG5) [41]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375-R cells; Skin; Homo sapiens (Human); CVCL_6234
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: G361/R cells; Skin; Homo sapiens (Human); CVCL_IW13
• In Vitro Model: MeWo cells; Skin; Homo sapiens (Human); CVCL_0445
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. miR216b suppresses autophagy in both BRAFi-sensitive and -resistant melanoma cells.

Key Molecule: Beclin-1 (BECN1) [41]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375-R cells; Skin; Homo sapiens (Human); CVCL_6234
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: G361/R cells; Skin; Homo sapiens (Human); CVCL_IW13
• In Vitro Model: MeWo cells; Skin; Homo sapiens (Human); CVCL_0445
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. miR216b suppresses autophagy in both BRAFi-sensitive and -resistant melanoma cells.

Key Molecule: hsa-mir-216b [41]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375-R cells; Skin; Homo sapiens (Human); CVCL_6234
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: G361/R cells; Skin; Homo sapiens (Human); CVCL_IW13
• In Vitro Model: MeWo cells; Skin; Homo sapiens (Human); CVCL_0445
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. miR216b suppresses autophagy in both BRAFi-sensitive and -resistant melanoma cells.

Key Molecule: UV radiation resistance-associated gene protein (UVRAG) [41]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375-R cells; Skin; Homo sapiens (Human); CVCL_6234
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: G361/R cells; Skin; Homo sapiens (Human); CVCL_IW13
• In Vitro Model: MeWo cells; Skin; Homo sapiens (Human); CVCL_0445
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. miR216b suppresses autophagy in both BRAFi-sensitive and -resistant melanoma cells.

Key Molecule: hsa-mir-7 [42]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Mel-CV cells; Skin; Homo sapiens (Human); CVCL_S996
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.

Key Molecule: hsa-mir-100 [43]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PLX4032-resistant cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CCL2 and miR-125b, miR-34a and miR-100 are potential targets for overcoming the miR-34a and miR-100 are potential targets for overcoming the resistance to BRAFi in melanoma.

Key Molecule: hsa-mir-125b [43]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PLX4032-resistant cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CCL2 and miR-125b, miR-34a and miR-100 are potential targets for overcoming the miR-34a and miR-100 are potential targets for overcoming the resistance to BRAFi in melanoma.

Key Molecule: hsa-mir-34 [43]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PLX4032-resistant cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CCL2 and miR-125b, miR-34a and miR-100 are potential targets for overcoming the miR-34a and miR-100 are potential targets for overcoming the resistance to BRAFi in melanoma.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: RAF proto-oncogene serine/threonine-protein kinase (RAF1) [42]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Mel-CV cells; Skin; Homo sapiens (Human); CVCL_S996
• Experiment for Molecule Alteration: Immunohistochemical staining assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.

Key Molecule: Epidermal growth factor receptor (EGFR) [42]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Mel-CV cells; Skin; Homo sapiens (Human); CVCL_S996
• Experiment for Molecule Alteration: Immunohistochemical staining assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [42]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Mel-CV cells; Skin; Homo sapiens (Human); CVCL_S996
• Experiment for Molecule Alteration: Immunohistochemical staining assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.

Key Molecule: Monocyte chemotactic and activating factor (CCL2) [43]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PLX4032-resistant cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CCL2 and miR-125b, miR-34a and miR-100 are potential targets for overcoming the miR-34a and miR-100 are potential targets for overcoming the resistance to BRAFi in melanoma.

Clinical Trial Drug(s) 22 drug(s) in total

Capivasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [44]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.H1968Y (c.5902C>T)
• Sensitive Drug: Capivasertib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 292T cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Cobimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Drug: Cobimetinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; .
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Crenolanib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.P577S (c.1729C>T)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.P577S (c.1729C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V658A (c.1973T>C)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.V658A (c.1973T>C) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.R841K (c.2522G>A)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.R841K (c.2522G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.H845Y (c.2533C>T)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.H845Y (c.2533C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G853D (c.2558G>A)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.G853D (c.2558G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.P577S (c.1729C>T)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.P577S (c.1729C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V658A (c.1973T>C)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.V658A (c.1973T>C) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.R841K (c.2522G>A)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.R841K (c.2522G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.H845Y (c.2533C>T)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.H845Y (c.2533C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [45]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G853D (c.2558G>A)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.G853D (c.2558G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target

Ganetespib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [46]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Ganetespib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

Refametinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [47]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Resistant Drug: Refametinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The missense mutation p.V600X (c.1798_1799) in gene BRAF cause the resistance of Refametinib by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [48]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Refametinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: BxPc3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Female athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Biochemical kinase assays
• Experiment for Drug Resistance: CellTiter 96 Aqueous One assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Refametinib by unusual activation of pro-survival pathway

Selumetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q56P (c.167A>C)
• Resistant Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.Q56P (c.167A>C) in gene MAP2K1 cause the resistance of Selumetinib by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.I103N (c.308T>A)
• Resistant Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.I103N (c.308T>A) in gene MAP2K1 cause the resistance of Selumetinib by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L115P (c.344T>C)
• Resistant Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.L115P (c.344T>C) in gene MAP2K1 cause the resistance of Selumetinib by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.P124S (c.370C>T)
• Resistant Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.P124S (c.370C>T) in gene MAP2K1 cause the resistance of Selumetinib by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.P124L (c.371C>T)
• Resistant Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.P124L (c.371C>T) in gene MAP2K1 cause the resistance of Selumetinib by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [50]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Resistant Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Guanine nucleotide-binding protein subunit alpha-11 (GNA11) [51]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Guanine nucleotide-binding protein subunit alpha-11 (GNA11) [51]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Guanine nucleotide-binding protein subunit alpha-11 (GNA11) [51]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Guanine nucleotide-binding protein subunit alpha-11 (GNA11) [51]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: GTPase Nras (NRAS) [52]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: MTD assay
• Mechanism Description: The missense mutation p.Q61L (c.182A>T) in gene NRAS cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [50]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Sensitive Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Key Molecule: GTPase Nras (NRAS) [52]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61R (c.182A>G)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: MTD assay
• Mechanism Description: The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [53]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Selumetinib by aberration of the drug's therapeutic target

Key Molecule: GTPase Nras (NRAS) [50]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G13D (c.38G>A)
• Sensitive Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Key Molecule: Cellular tumor antigen p53 (TP53) [50]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.D259Y (c.775G>T)
• Sensitive Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Vemurafenib/Cobimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [54]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Sensitive Drug: Vemurafenib/Cobimetinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Drug: Vemurafenib/Cobimetinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Vemurafenib/Cobimetinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Vemurafenib/Cobimetinib
• Experimental Note: Identified from the Human Clinical Data

E6201

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [55]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: E6201
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: MDA-MB-435s cells; Breast; Homo sapiens (Human); CVCL_0622
• In Vitro Model: SEKI cells; Skin; Homo sapiens (Human); CVCL_3162
• In Vitro Model: HMV-1 cells; Uterus; Homo sapiens (Human); CVCL_8233
• In Vitro Model: HMCB cells; Skin; Homo sapiens (Human); CVCL_3317
• In Vitro Model: CHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_1122
• Experiment for Molecule Alteration: Western blotting analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: WST-8 assay

Pictilisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [56]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Pictilisib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ICH assay
• Experiment for Drug Resistance: Plasma level assay; Electrochemiluminescense assay

RAF-265

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [57]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: RAF-265
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; .

RO-5126766 free base

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [58]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: RO-5126766 free base
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: SUM-52PE cells; Pleural effusion; Homo sapiens (Human); CVCL_3425
• In Vitro Model: NCI-H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vitro Model: KMS-11 cells; Pleural effusion; Homo sapiens (Human); CVCL_2989
• In Vitro Model: HSC-39 cells; Ascites; Homo sapiens (Human); CVCL_A385
• In Vitro Model: DMS-114 cells; Lung; Homo sapiens (Human); CVCL_1174
• In Vitro Model: AN3 CA cells; Endometrium; Homo sapiens (Human); CVCL_0028
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: KATO-III cells; Pleural effusion; Homo sapiens (Human); CVCL_0371
• In Vitro Model: AN3 CA cells; Endometrium; Homo sapiens (Human); CVCL_0028
• Experiment for Molecule Alteration: Microarray assay; Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Tanespimycin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [59]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G13D (c.38G>A)
• Sensitive Drug: Tanespimycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human melanoma tissue; .
• Mechanism Description: The missense mutation p.G13D (c.38G>A) in gene NRAS cause the sensitivity of Tanespimycin by unusual activation of pro-survival pathway

Ulixertinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [60]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Ulixertinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vivo Model: Athymic nude mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Standard coupled-enzyme assay

Uprosertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [61]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Drug: Uprosertib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 19 drug na?ve cell lines and four sub-lines; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ATP-based luminescent assay; Flow cytometry assay

Agerafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [62]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Agerafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Agerafenib by aberration of the drug's therapeutic target

Lifirafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [63]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Lifirafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Female NOD/SCID and BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

BI-847325

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [64]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: BI-847325
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM793 cells; N.A.; Homo sapiens (Human); CVCL_8787/CVCL_5414
• In Vitro Model: WM39 cells; Skin; Homo sapiens (Human); CVCL_2240
• In Vitro Model: WM164 cells; Skin; Homo sapiens (Human); CVCL_7928
• In Vitro Model: RPMI-7951 cells; Lymph node; Homo sapiens (Human); CVCL_1666
• In Vitro Model: 1205Lu cells; Skin; Homo sapiens (Human); CVCL_5239
• In Vivo Model: BALB SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; qPCR; Proteasome-Glo Chymotrypsin-like cell-based assay
• Experiment for Drug Resistance: Alamar blue assay; Colony formation assay

GSK126

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [65]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Y641S (c.1922A>C)
• Sensitive Drug: GSK126
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; .
• Experiment for Molecule Alteration: Western blotting analysis; BCA assay
• Mechanism Description: EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [65]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Y641N (c.1921T>A)
• Sensitive Drug: GSK126
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; .
• Experiment for Molecule Alteration: Western blotting analysis; BCA assay
• Mechanism Description: EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [65]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Y641H (c.1921T>C)
• Sensitive Drug: GSK126
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; .
• Experiment for Molecule Alteration: Western blotting analysis; BCA assay
• Mechanism Description: EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [66]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Y646N (c.1936T>A)
• Sensitive Drug: GSK126
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SKMEL-28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: MM386 cells; Lymph node; Homo sapiens (Human); CVCL_2607
• In Vitro Model: MM200 cells; Skin; Homo sapiens (Human); CVCL_C836
• In Vitro Model: MEL-RM cells; Lymph node; Homo sapiens (Human); CVCL_D548
• In Vitro Model: MEL-JD cells; Lymph node; Homo sapiens (Human); CVCL_BS80
• In Vitro Model: ME4405 cells; Skin; Homo sapiens (Human); CVCL_C680
• In Vitro Model: ME1007 cells; Skin; Homo sapiens (Human); CVCL_C668
• In Vitro Model: IGR1 Mel-RMU cells; Lymph node; Homo sapiens (Human); CVCL_S994
• In Vitro Model: HEM cells; N.A.; .; N.A.
• In Vitro Model: HDF cells; N.A.; .; N.A.
• In Vitro Model: C001 cells; Skin; Homo sapiens (Human); CVCL_B4K8
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [66]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Y646N (c.1936T>A)
• Sensitive Drug: GSK126
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SKMEL-28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: MM386 cells; Lymph node; Homo sapiens (Human); CVCL_2607
• In Vitro Model: MM200 cells; Skin; Homo sapiens (Human); CVCL_C836
• In Vitro Model: MEL-RM cells; Lymph node; Homo sapiens (Human); CVCL_D548
• In Vitro Model: MEL-JD cells; Lymph node; Homo sapiens (Human); CVCL_BS80
• In Vitro Model: ME4405 cells; Skin; Homo sapiens (Human); CVCL_C680
• In Vitro Model: ME1007 cells; Skin; Homo sapiens (Human); CVCL_C668
• In Vitro Model: IGR1 Mel-RMU cells; Lymph node; Homo sapiens (Human); CVCL_S994
• In Vitro Model: HEM cells; N.A.; .; N.A.
• In Vitro Model: HDF cells; N.A.; .; N.A.
• In Vitro Model: C001 cells; Skin; Homo sapiens (Human); CVCL_B4K8
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

LY-294002

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [44]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.H1968Y (c.5902C>T)
• Sensitive Drug: LY-294002
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 292T cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

LY3009120

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [50]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Resistant Drug: LY3009120
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Drug: LY3009120
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; .
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [50]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: LY3009120
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Key Molecule: GTPase Nras (NRAS) [50]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Sensitive Drug: LY3009120
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Key Molecule: GTPase Nras (NRAS) [50]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G13D (c.38G>A)
• Sensitive Drug: LY3009120
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Key Molecule: Cellular tumor antigen p53 (TP53) [50]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.D259Y (c.775G>T)
• Sensitive Drug: LY3009120
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Omipalisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [67]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Drug: Omipalisib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600K (c.1798_1799delGTinsAA) in gene BRAF cause the sensitivity of Omipalisib by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [67]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Omipalisib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Omipalisib by unusual activation of pro-survival pathway

PLX4720

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Guanine nucleotide-binding protein alpha-q (GNAQ) [68]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Resistant Drug: PLX4720
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Sanger sequencing assay; SNP array; qPCR
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q56P (c.167A>C)
• Resistant Drug: PLX4720
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.Q56P (c.167A>C) in gene MAP2K1 cause the resistance of PLX4720 by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [69]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Resistant Drug: PLX4720
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [70]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: PLX4720
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target

Discontinued Drug(s) 1 drug(s) in total

RO4987655

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [71]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Sensitive Drug: RO4987655
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; .
• Experiment for Molecule Alteration: IHC assay; Tumor-DNA mutation analysis
• Experiment for Drug Resistance: Pharmacokinetics analysis; Tumor biopsies analysis

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [58]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: RO4987655
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: SUM-52PE cells; Pleural effusion; Homo sapiens (Human); CVCL_3425
• In Vitro Model: NCI-H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vitro Model: KMS-11 cells; Pleural effusion; Homo sapiens (Human); CVCL_2989
• In Vitro Model: HSC-39 cells; Ascites; Homo sapiens (Human); CVCL_A385
• In Vitro Model: DMS-114 cells; Lung; Homo sapiens (Human); CVCL_1174
• In Vitro Model: AN3 CA cells; Endometrium; Homo sapiens (Human); CVCL_0028
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: KATO-III cells; Pleural effusion; Homo sapiens (Human); CVCL_0371
• In Vitro Model: AN3 CA cells; Endometrium; Homo sapiens (Human); CVCL_0028
• Experiment for Molecule Alteration: Microarray assay; Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Preclinical Drug(s) 28 drug(s) in total

BI-69A11

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [72]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: BI-69A11
• Experimental Note: Identified from the Human Clinical Data

Buparlisib/Vemurafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [73]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Drug: Buparlisib/Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: SK cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Fluorescent microscopy assay; Apoptosis analysis

CCT196969

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [74]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Sensitive Drug: CCT196969
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [69]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: CCT196969
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female xenograft nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Sanger Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

Key Molecule: GTPase Nras (NRAS) [69]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Drug: CCT196969
• Experimental Note: Identified from the Human Clinical Data

CCT241161

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [74]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Sensitive Drug: CCT241161
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [69]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: CCT241161
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female xenograft nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Sanger Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

Key Molecule: GTPase Nras (NRAS) [69]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Drug: CCT241161
• Experimental Note: Identified from the Human Clinical Data

Cediranib/PLX4720

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [75]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Cediranib/PLX4720
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM451 cells; Skin; Homo sapiens (Human); CVCL_6357
• In Vivo Model: Nu/Nu(ISTMel1) mouse xenograft model; NSG (RPMI7951) female mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: CellTiter-Glo assay

DEL-22379

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [76]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: DEL-22379
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 luminogenic assay

DETD-35

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [77]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: DETD-35
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: STAT3 signaling pathway; Inhibition; hsa04550
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: MeWo cells; Skin; Homo sapiens (Human); CVCL_0445
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: B16-F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vitro Model: SkMEL2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: BRAF cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunohistochemistry analysis
• Experiment for Drug Resistance: MTT assay; Crystal violet staining assay; FACS assay
• Mechanism Description: DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells.

EBI-907

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [78]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: EBI-907
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SW-480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: Colo-205 cells; Ascites; Homo sapiens (Human); CVCL_0218
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: Nu/Nu Colo-205 xenograft mouse model; Nu/Nu A357 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay

Ganetespib/TAK-733

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [46]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Ganetespib/TAK-733
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

GDC0879

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [79]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: GDC0879
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of GDC0879 by aberration of the drug's therapeutic target

INU-152

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [80]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: INU-152
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: SkMEL2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: Colo-205 cells; Ascites; Homo sapiens (Human); CVCL_0218
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: INU-152 inhibits all RAF isoforms and inhibits MAPK pathways in mutant BRAF cells. More importantly, INU-152 exhibits minimal paradoxical pathway activation in melanoma cells with mutant RAS. INU-152 exhibits anti-tumor activities in xenograft models carrying BRAF mutations.

LY-294002/Capivasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [44]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.P2213S (c.6637C>T)
• Sensitive Drug: LY-294002/Capivasertib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 292T cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [44]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.P2213S (c.6637C>T)
• Sensitive Drug: LY-294002/Capivasertib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 292T cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

MK-2206/PD184352

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [68]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: FS-deletion; p.V317fs (c.950_953)
• Sensitive Drug: MK-2206/PD184352
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Sanger sequencing assay; SNP array; qPCR
• Experiment for Drug Resistance: CellTiter-Glo assay

MK2206/Vemurafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [73]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Drug: MK2206/Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: SK cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Fluorescent microscopy assay; Apoptosis analysis

Palbociclib/PD-0325901

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [81]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Palbociclib/PD-0325901
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6 signaling pathway; Regulation; hsa04218
• Cell Pathway Regulation: MEK signaling pathway; Inhibition; hsa04011
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: SKMEL207 cells; Skin; Homo sapiens (Human); CVCL_6108
• In Vitro Model: SBCL2 cells; Skin; Homo sapiens (Human); CVCL_D732
• In Vitro Model: CHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_1122
• In Vitro Model: BOWES cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: 1205Lu cells; Skin; Homo sapiens (Human); CVCL_5239
• In Vivo Model: Female athymic mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay; Crystal violet staining assay
• Mechanism Description: In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking.

PLX7904

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G466E (c.1397G>A)
• Resistant Drug: PLX7904
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.G466E (c.1397G>A) in gene BRAF cause the resistance of PLX7904 by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600R (c.1798_1799delGTinsAG)
• Sensitive Drug: PLX7904
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600R (c.1798_1799delGTinsAG) in gene BRAF cause the sensitivity of PLX7904 by aberration of the drug's therapeutic target

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Sensitive Drug: PLX7904
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600D (c.1799_1800delTGinsAC) in gene BRAF cause the sensitivity of PLX7904 by aberration of the drug's therapeutic target

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [83]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: PLX7904
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: SkMEL239-C3 cells; Skin; Homo sapiens (Human); CVCL_6122
• In Vitro Model: SkMEL239 cells; Skin; Homo sapiens (Human); CVCL_6122
• In Vitro Model: IPC-298 cells; Skin; Homo sapiens (Human); CVCL_1307
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vitro Model: B9 cells; N.A.; Mus musculus (Mouse); CVCL_1952
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Microarray gene expression analysis; Crystallization and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Anchorage-independent growth assay

RAF709

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [84]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: RAF709
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.

Key Molecule: GTPase Nras (NRAS) [84]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Sensitive Drug: RAF709
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.

Key Molecule: GTPase Nras (NRAS) [84]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Drug: RAF709
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.

RMC-4550

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [85]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Resistant Drug: RMC-4550
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS/RAF/MEK/ERK signaling pathway; Activation; hsa01521
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Nras cells; N.A.; .; N.A.
• In Vitro Model: NCI-H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: KRAS cells; N.A.; .; N.A.
• In Vitro Model: Hras cells; N.A.; .; N.A.
• In Vivo Model: Athymic Balb/C nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading.

S3I-201

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [86]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: S3I-201
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of S3I-201 by unusual activation of pro-survival pathway

SB590885

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: SB590885
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of SB590885 by aberration of the drug's therapeutic target

SBI-0640726

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [72]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: SBI-0640726
• Experimental Note: Identified from the Human Clinical Data

SBI-0640756

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [72]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: SBI-0640756
• Experimental Note: Identified from the Human Clinical Data

SBI-755199

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [72]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: SBI-755199
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Crystal violet staining assay

SEL201

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [87]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L576P (c.1727T>C)
• Sensitive Drug: SEL201
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MM61 cells; N.A.; .; N.A.
• In Vitro Model: MM111 cells; N.A.; .; N.A.
• In Vitro Model: M230 cells; Skin; Homo sapiens (Human); CVCL_D749
• In Vitro Model: LND1 cells; Skin; Homo sapiens (Human); CVCL_J076
• In Vitro Model: HBL cells; Skin; Homo sapiens (Human); CVCL_J075
• In Vivo Model: CD-1 mouse PDX model; Mus musculus
• Experiment for Drug Resistance: SRB assay; Crystal violet staining assay; Promega assay
• Mechanism Description: c-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [87]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.D820Y (c.2458G>T)
• Sensitive Drug: SEL201
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MM61 cells; N.A.; .; N.A.
• In Vitro Model: MM111 cells; N.A.; .; N.A.
• In Vitro Model: M230 cells; Skin; Homo sapiens (Human); CVCL_D749
• In Vitro Model: LND1 cells; Skin; Homo sapiens (Human); CVCL_J076
• In Vitro Model: HBL cells; Skin; Homo sapiens (Human); CVCL_J075
• In Vivo Model: CD-1 mouse PDX model; Mus musculus
• Experiment for Drug Resistance: SRB assay; Crystal violet staining assay; Promega assay
• Mechanism Description: c-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins.

Selumetinib/Dactolisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [88]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Selumetinib/Dactolisib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BRAF-mutant melanoma cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Selumetinib/Vemurafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [73]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Drug: Selumetinib/Vemurafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: SK cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Fluorescent microscopy assay; Apoptosis analysis

TAK-632

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G466E (c.1397G>A)
• Sensitive Drug: TAK-632
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.G466E (c.1397G>A) in gene BRAF cause the sensitivity of TAK-632 by aberration of the drug's therapeutic target

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600R (c.1798_1799delGTinsAG)
• Sensitive Drug: TAK-632
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600R (c.1798_1799delGTinsAG) in gene BRAF cause the sensitivity of TAK-632 by aberration of the drug's therapeutic target

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: TAK-632
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of TAK-632 by aberration of the drug's therapeutic target

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Sensitive Drug: TAK-632
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600D (c.1799_1800delTGinsAC) in gene BRAF cause the sensitivity of TAK-632 by aberration of the drug's therapeutic target

Unspecified VEGFR2 antibody

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: VEGF-2 receptor (KDR) [89]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q472H (c.1416A>T)
• Sensitive Drug: Unspecified VEGFR2 antibody
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: WM3248 cells; Skin; Homo sapiens (Human); CVCL_6798
• In Vitro Model: WM1575 cells; Skin; Homo sapiens (Human); CVCL_L027
• Experiment for Molecule Alteration: Targeted NGS assay
• Experiment for Drug Resistance: Proliferation assay; Invasion assay

Investigative Drug(s) 17 drug(s) in total

AZ628

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G466E (c.1397G>A)
• Sensitive Drug: AZ628
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.G466E (c.1397G>A) in gene BRAF cause the sensitivity of AZ628 by aberration of the drug's therapeutic target

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600R (c.1798_1799delGTinsAG)
• Sensitive Drug: AZ628
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600R (c.1798_1799delGTinsAG) in gene BRAF cause the sensitivity of AZ628 by aberration of the drug's therapeutic target

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: AZ628
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of AZ628 by aberration of the drug's therapeutic target

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Sensitive Drug: AZ628
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600D (c.1799_1800delTGinsAC) in gene BRAF cause the sensitivity of AZ628 by aberration of the drug's therapeutic target

Bevacizumab/Sorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [90]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L576P (c.1727T>C)
• Sensitive Drug: Bevacizumab/Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ICH assay
• Experiment for Drug Resistance: Radiologic assessment assay

Binimetinib/Encorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [91]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Binimetinib/Encorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [91]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Drug: Binimetinib/Encorafenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [91]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Drug: Binimetinib/Encorafenib
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Drug: Binimetinib/Encorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; .
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [92]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Sensitive Drug: Binimetinib/Encorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; .

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [92]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Sensitive Drug: Binimetinib/Encorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; .

Braf inhibitor

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [93]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Braf inhibitor
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: Data suggest that the presence of mutated NRAS in the melanoma cell population in parallel with mutated BRAF cells results in resistance to BRAF inhibitors, most probably selecting NRAS-mutated cells in the advancing tumor.

Key Molecule: Homeobox protein Hox-D8 (HOXD8) [93]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Braf inhibitor
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: Earlier, it was demonstrated that RAC1codon29 mutant melanomas are resistant to this therapy. Later, it was found that a rare genetic alteration, the mutation of HOXD8, can also be the cause of primary resistance to BRAF inhibitors.

BRAF/MEK inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: MAPK/ERK kinase 2 (MEK2) [94]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.Q60P (c.179A>C)
• Resistant Drug: BRAF/MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter96 AQueous assay

Celastrol

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-217 [21]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Celastrol
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

Key Molecule: hsa-mir-335 [21]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Celastrol
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-200b [21]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Celastrol
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

Key Molecule: hsa-miR-326 [21]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Celastrol
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vitro Model: Malme3M cells; Skin; Homo sapiens (Human); CVCL_1438
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.

CI-1040

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.I103N (c.308T>A)
• Resistant Drug: CI-1040
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.I103N (c.308T>A) in gene MAP2K1 cause the resistance of CI-1040 by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L115P (c.344T>C)
• Resistant Drug: CI-1040
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.L115P (c.344T>C) in gene MAP2K1 cause the resistance of CI-1040 by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Hras (HRAS) [76]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• Sensitive Drug: CI-1040
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 luminogenic assay

Cisplatinum

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: H19, imprinted maternally expressed transcript (H19) [95]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: Cisplatinum
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: M8 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM35 cells; Skin; Homo sapiens (Human); CVCL_0580
• In Vitro Model: SK-MEL-2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: A2508 cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Knockdown assay; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulation of LncRNA H19 sensitizes melanoma cells to cisplatin by regulating the miR-18b/IGF1 axis.

Cobimetinib/Vemurafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [96]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Drug: Cobimetinib/Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Gardiquimod

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [97]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gardiquimod
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Resazurin Cell Viability Assay
• Mechanism Description: Imidazoquinolines IMQ, RSQ, and GDQ are substrates for P-gp and begins to elucidate differences in their trafficking in cancer cells as a consequence of acquired drug resistance. We believe this work that begins to examine imidazoquinoline trafficking will prove useful in the future rational design of immunotherapeutics with enhanced susceptibility to P-gp efflux that enable increased bioavailability, in MDR cancers.

Imiquimod

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [97]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Imiquimod
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Resazurin Cell Viability Assay
• Mechanism Description: Imidazoquinolines IMQ, RSQ, and GDQ are substrates for P-gp and begins to elucidate differences in their trafficking in cancer cells as a consequence of acquired drug resistance. We believe this work that begins to examine imidazoquinoline trafficking will prove useful in the future rational design of immunotherapeutics with enhanced susceptibility to P-gp efflux that enable increased bioavailability, in MDR cancers.

MEK inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.P124L (c.371C>T)
• Resistant Drug: MEK inhibitors
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.P124L (c.371C>T) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 2 (MEK2) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.N126D (c.376A>G)
• Resistant Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: MAPK/ERK kinase 2 (MEK2) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V35M (c.103G>A)
• Resistant Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: MAPK/ERK kinase 2 (MEK2) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L46F (c.136C>T)
• Resistant Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: MAPK/ERK kinase 2 (MEK2) [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.C125S (c.373T>A)
• Resistant Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [98]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K57N (c.171G>C)
• Resistant Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.K57N (c.171G>C) in gene MAP2K1 cause the resistance of MEK inhibitors by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [99]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.C121S (c.361T>A)
• Resistant Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human melanoma tissue; .
• Mechanism Description: The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of MEK inhibitors by unusual activation of pro-survival pathway

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [30]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597R (c.1790T>G)
• Sensitive Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [31]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.D594A (c.1781A>C)
• Sensitive Drug: MEK inhibitors
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.D594A (c.1781A>C) in gene BRAF cause the sensitivity of MEK inhibitors by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [31]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K483M (c.1448_1449delAAinsTG)
• Sensitive Drug: MEK inhibitors
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.K483M (c.1448_1449delAAinsTG) in gene BRAF cause the sensitivity of MEK inhibitors by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [29]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K601R (c.1802A>G)
• Sensitive Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; .
• Mechanism Description: The missense mutation p.K601R (c.1802A>G) in gene BRAF cause the sensitivity of MEK inhibitors by unusual activation of pro-survival pathway

Orthocresol

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Growth arrest specific 5 (GAS5) [100]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Orthocresol
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: 2-O-Methylmagnolol upregulates the long non-coding RNA, GAS5, and enhances apoptosis in skin cancer cells. Overexpression of LncRNA GAS5 inhibited cell proliferation and promoted cell apoptosis in skin cancer cells.

Resiquimod

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [97]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Resiquimod
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Resazurin Cell Viability Assay
• Mechanism Description: Imidazoquinolines IMQ, RSQ, and GDQ are substrates for P-gp and begins to elucidate differences in their trafficking in cancer cells as a consequence of acquired drug resistance. We believe this work that begins to examine imidazoquinoline trafficking will prove useful in the future rational design of immunotherapeutics with enhanced susceptibility to P-gp efflux that enable increased bioavailability, in MDR cancers.

SCH772984

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [76]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: SCH772984
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 luminogenic assay

TAK-733

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [28]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Drug: TAK-733
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [28]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Drug: TAK-733
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway

U0126

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [101]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.G469E (c.1406G>A)
• Resistant Drug: U0126
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human melanoma tissue; .
• In Vivo Model: (SCID) CB-17 mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.G469E (c.1406G>A) in gene BRAF cause the resistance of U0126 by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [101]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.D594G (c.1781A>G)
• Resistant Drug: U0126
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human melanoma tissue; .
• In Vivo Model: (SCID) CB-17 mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.D594G (c.1781A>G) in gene BRAF cause the resistance of U0126 by unusual activation of pro-survival pathway

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