Molecule Information

General Information of the Molecule (ID: Mol00593)

• Name: GTPase Nras (NRAS) ,Homo sapiens
• Synonyms: Transforming protein N-Ras; HRAS1
• Molecule Type: Protein
• Gene Name: NRAS
• Gene ID: 4893
• Location: chr1:114704469-114716771[-]
• Sequence:
  MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
  QEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDL
  PTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQG
  CMGLPCVVM
• Function: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
• Uniprot ID: RASN_HUMAN
• Ensembl ID: ENSG00000213281
• HGNC ID: HGNC:7989

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 19 drug(s) in total

Binimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Binimetinib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• 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

Disease Class: Melanoma [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Binimetinib
• Molecule Alteration: Missense mutation; p.Q61R (c.182A>G)
• 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

Disease Class: Melanoma [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Binimetinib
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• 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

Disease Class: Melanoma [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Binimetinib
• Molecule Alteration: Missense mutation; p.Q61R (c.182A>G)
• 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

Disease Class: Melanoma [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Binimetinib
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• 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

Bosutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [2], [3]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Bosutinib
• Molecule Alteration: Missense mutation; p.G12V
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT signaling pathway; Activation; hsa04030
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

Cetuximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Metastatic colorectal cancer [4]

• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Resistant Drug: Cetuximab
• Molecule Alteration: Missense mutation; p.G12C
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Inhibition; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsies assay; Functional analyses of cell populations assay
• Mechanism Description: Acquired resistance to EGFR blockade is driven by the emergence of kRAS/NRAS mutations or the development of EGFR extracellular domain (ECD) variants, which impair antibody binding.

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [5]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Caspase-3 Activity Assay
• Mechanism Description: miR-29a renders lung cancer cells more sensitive to cisplatin treatment and miR-29a and cisplatin combination promoted apoptotic effect through targeting NRAS in lung cancer cells.

Disease Class: Gastric cancer [6]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• 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: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: NRAS and E2F2 as the direct targets of miR-26a were further confirmed in luciferase activity assays and miR-26a-mediated these two genes expression analysis. Our results also found that knockdown of NRAS or E2F2 sensitize GC cells to cisplatin. miR-26a overexpression has been demonstrated to improve the sensitivity of GC cells to cisplatin and this effect was considered to be mediated via its targets NRAS and E2F2.

Dabrafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [7], [8], [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.Q61K
• 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.

Disease Class: Melanoma [9], [10]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.Q61R
• 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.

Disease Class: Melanoma [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.Q61L
• 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.

Disease Class: Melanoma [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.G13R
• 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.

Disease Class: Melanoma [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.G12R
• 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.

Disease Class: Melanoma [9], [11]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.G12D
• 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.

Dasatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [2], [3]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Missense mutation; p.G12V
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT signaling pathway; Activation; hsa04030
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [2], [3]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.G12V
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT signaling pathway; Activation; hsa04030
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

Lapatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.V14A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.F78L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.F28S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.A66T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Nilotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [2], [3]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Nilotinib
• Molecule Alteration: Missense mutation; p.G12V
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT signaling pathway; Activation; hsa04030
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [13]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDM231 cells; Breast; Homo sapiens (Human); CVCL_5T76
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: microRNA-22 sensitized breast cancer cells to paclitaxel by downregulation of NRAS.

Pamidronate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [14]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Pamidronate
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: Pseudomonas aeruginosa strain B-730P/17; 287
• Experiment for Drug Resistance: CellTiter 96 one solution proliferation assay
• Mechanism Description: In response to pamidronate, there was significant inhibition of cell proliferation in MDA-231 and SKBR-3 cells, compared to MDA-175 cells. This correlated with their respective basal levels of N-ras and H-ras. N-ras and H-ras protein levels were both reduced in MDA-231 cells, and to lesser extent in SKBR-3 cells, following exposure to pamidronate, whereas these markers were not altered in MDA-175 cells, resistance to pamidronate may result from low levels of GTPase-activating proteins, such as N-ras and H-ras, in tumor cells.

Panitumumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Metastatic colorectal cancer [4]

• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Resistant Drug: Panitumumab
• Molecule Alteration: Missense mutation; p.G12C
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Inhibition; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsies assay; Functional analyses of cell populations assay
• Mechanism Description: Acquired resistance to EGFR blockade is driven by the emergence of kRAS/NRAS mutations or the development of EGFR extracellular domain (ECD) variants, which impair antibody binding.

Disease Class: Colorectal cancer [15]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Panitumumab
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Disease Class: Colorectal cancer [16]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Panitumumab
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Mechanism Description: Mutations in kRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment.

Pembrolizumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [17]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Pembrolizumab
• Molecule Alteration: Missense mutation; p.Q61R
• 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.

Pertuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.V14A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.F78L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.F28S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.A66T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Ponatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [2], [3]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.G12V
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT signaling pathway; Activation; hsa04030
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [18]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: SW1271 cells; Lung; Homo sapiens (Human); CVCL_1716
• In Vitro Model: H2347 cells; Lung; Homo sapiens (Human); CVCL_1550
• In Vitro Model: H2087 cells; Lymph node; Homo sapiens (Human); CVCL_1524
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Cell Titer blue reagent assay
• Mechanism Description: The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Trastuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.V14A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.F78L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.F28S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.A66T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Trastuzumab emtansine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.V14A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.F78L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.F28S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [12]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.A66T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Vemurafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Multiple myeloma [19]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.Q61H
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Ion Torrent semiconductor-based targeted resequencing assay
• Experiment for Drug Resistance: Whole-body magnetic resonance imaging (MRI) assay
• Mechanism Description: Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).

Disease Class: Multiple myeloma [19]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.G13R
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Ion Torrent semiconductor-based targeted resequencing assay
• Experiment for Drug Resistance: Whole-body magnetic resonance imaging (MRI) assay
• Mechanism Description: Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).

Disease Class: Multiple myeloma [19]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.G12A
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Ion Torrent semiconductor-based targeted resequencing assay
• Experiment for Drug Resistance: Whole-body magnetic resonance imaging (MRI) assay
• Mechanism Description: Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).

Disease Class: Melanoma [7]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.Q61H
• 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.

Disease Class: Melanoma [7], [9], [20]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.Q61R
• 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.

Disease Class: Melanoma [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.Q61L
• 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.

Disease Class: Melanoma [7], [9], [20]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.Q61K
• 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.

Disease Class: Melanoma [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.G13R
• 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.

Disease Class: Melanoma [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.G12R
• 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.

Disease Class: Melanoma [9]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.G12D
• 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.

Disease Class: Melanoma [21], [22]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.Q61K
• 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.

Disease Class: Melanoma [23]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.Q61K
• 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.

Disease Class: Melanoma [23]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.Q61K
• 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.

Clinical Trial Drug(s) 4 drug(s) in total

Selumetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [24]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• 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)

Disease Class: Lung adenocarcinoma [18]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: SW1271 cells; Lung; Homo sapiens (Human); CVCL_1716
• In Vitro Model: H2347 cells; Lung; Homo sapiens (Human); CVCL_1550
• In Vitro Model: H2087 cells; Lymph node; Homo sapiens (Human); CVCL_1524
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Cell Titer blue reagent assay
• Mechanism Description: The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway

Disease Class: Melanoma [25]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• 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

Disease Class: Melanoma [24]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• 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

Disease Class: Melanoma [25]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.Q61R (c.182A>G)
• 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

Disease Class: Melanoma [26]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• 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

Disease Class: Melanoma [24]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.G13D (c.38G>A)
• 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

Tanespimycin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [27]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Tanespimycin
• Molecule Alteration: Missense mutation; p.G13D (c.38G>A)
• 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

LY3009120

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [24]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: LY3009120
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• 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)

Disease Class: Melanoma [24]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: LY3009120
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• 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

Disease Class: Melanoma [24]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: LY3009120
• Molecule Alteration: Missense mutation; p.G13D (c.38G>A)
• 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

PLX4720

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [28]

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

Preclinical Drug(s) 10 drug(s) in total

Alpelisib/Binimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Alveolar rhabdomyosarcoma [29]

• Sensitive Disease: Alveolar rhabdomyosarcoma [ICD-11: 2B55.0]
• Sensitive Drug: Alpelisib/Binimetinib
• Molecule Alteration: Missense mutation; p.Q61H (c.183A>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAF/MEK/ERK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RMS cells; Soft tissue; Homo sapiens (Human); CVCL_W527
• In Vivo Model: Chorioallantoic membrane; Gallus gallus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay; FACS; crystal violet staining
• Mechanism Description: Coinhibition of NRAS or MEK plus PI3Kalpha triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kalpha-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS- or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo.

Disease Class: Acute myeloid leukemia [30]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Alpelisib/Binimetinib
• Molecule Alteration: Missense mutation; p.G12D (c.35G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NOMO1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• In Vitro Model: THP1 cell; Peripheral blood; Homo sapiens (Human); CVCL_0006
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

CCT196969

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [28]

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

CCT241161

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [28]

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

Cetuximab/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [31]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Cetuximab/Trametinib
• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: CCK-81 cells; N.A.; Homo sapiens (Human); CVCL_2873

Compound 3144

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: T-cell lymphoma [32]

• Sensitive Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Sensitive Drug: Compound 3144
• Molecule Alteration: Missense mutation; p.G13D (c.38G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RAS signaling pathway; Inhibition; hsa04014
• In Vitro Model: MEF cells; Bone marrow; Homo sapiens (Human); CVCL_M515
• In Vivo Model: Athymic nude Nu/Nu mouse PDX model; Mus musculus

Everolimus/Binimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Neuroblastoma [33]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Sensitive Drug: Everolimus/Binimetinib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: NGP cells; Lung; Homo sapiens (Human); CVCL_2141
• In Vitro Model: CHP-212 cells; Brain; Homo sapiens (Human); CVCL_1125
• In Vitro Model: CHP-134 cells; Adrenal gland; Homo sapiens (Human); CVCL_1124
• Experiment for Molecule Alteration: Western blotting analysis; PCR
• Experiment for Drug Resistance: Promega assay; FACS assay
• Mechanism Description: Combination of mTOR and MEK inhibitors synergistically inhibit downstream signaling and cell growth of NRAS mutant cell lines.

MK2206

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Thyroid gland cancer [34]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.Q61R (c.182A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Pimasertib/Regorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [35]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Pimasertib/Regorafenib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vivo Model: Female balb/c athymic (nu+/nu+) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Pimasertib + Regorafenib by unusual activation of pro-survival pathway

Disease Class: Lung adenocarcinoma [35]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Pimasertib/Regorafenib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vivo Model: Female balb/c athymic (nu+/nu+) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Pimasertib + Regorafenib by unusual activation of pro-survival pathway

RAF709

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [36]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: RAF709
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• 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.

Disease Class: Melanoma [36]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: RAF709
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• 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.

Disease Class: Melanoma [36]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: RAF709
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• 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.

Selumetinib/Dactolisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [37]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Selumetinib/Dactolisib
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Liver; .
• In Vivo Model: Female nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Mechanism Description: The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Selumetinib + Dactolisib by unusual activation of pro-survival pathway

Investigative Drug(s) 4 drug(s) in total

Braf inhibitor

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [38]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Braf inhibitor
• Molecule Alteration: Mutation; .
• 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.

ERK inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [39]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: ERK inhibitors
• Molecule Alteration: Missense mutation; p.G12C (c.34G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Fluorescence-activated cell sorting assay
• Mechanism Description: The missense mutation p.G12C (c.34G>T) in gene NRAS cause the sensitivity of ERK inhibitors by unusual activation of pro-survival pathway

N-arachidonoyl dopamine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [40]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: N-arachidonoyl dopamine
• Molecule Alteration: Missense mutation; p.G12D (c.35G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: WEHI-3 cells; Peripheral blood; Mus musculus (Mouse); CVCL_3622
• In Vitro Model: Bosc23 cells; Fetal kidney; Homo sapiens (Human); CVCL_4401
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation.

PKI-587

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [41]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: PKI-587
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Experimental Note: Identified from the Human Clinical Data

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.15E-106; Fold-change: 8.77E-01; Z-score: 1.64E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.97E-01; Fold-change: 1.73E-01; Z-score: 1.11E+00
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.93E-01; Fold-change: 1.25E-02; Z-score: 2.72E-02
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.85E-06; Fold-change: 1.63E+00; Z-score: 2.78E+00

Chronic myeloid leukemia [ICD-11: 2A20]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Whole blood
• The Specified Disease: Myelofibrosis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.61E-01; Fold-change: 1.78E-01; Z-score: 5.30E-01
• The Studied Tissue: Whole blood
• The Specified Disease: Polycythemia vera
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.11E-01; Fold-change: 7.31E-02; Z-score: 2.22E-01

Acute myeloid leukemia [ICD-11: 2A60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bone marrow
• The Specified Disease: Acute myeloid leukemia
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.75E-30; Fold-change: 6.11E-01; Z-score: 1.46E+00

Multiple myeloma [ICD-11: 2A83]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bone marrow
• The Specified Disease: Multiple myeloma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.29E-04; Fold-change: 5.38E-01; Z-score: 2.03E+00
• The Studied Tissue: Peripheral blood
• The Specified Disease: Multiple myeloma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.65E-01; Fold-change: -1.61E-01; Z-score: -4.70E-01

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.88E-01; Fold-change: 7.15E-01; Z-score: 6.55E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.81E-04; Fold-change: 4.36E-01; Z-score: 1.21E+00

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.97E-31; Fold-change: 4.05E-01; Z-score: 1.15E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.00E-14; Fold-change: 3.26E-01; Z-score: 7.34E-01

Melanoma [ICD-11: 2C30]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Melanoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.02E-03; Fold-change: 3.94E-01; Z-score: 6.83E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.25E-26; Fold-change: 3.50E-01; Z-score: 6.95E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.60E-04; Fold-change: 2.12E-01; Z-score: 2.99E-01

Thyroid cancer [ICD-11: 2D10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Thyroid
• The Specified Disease: Thyroid cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.65E-01; Fold-change: 3.79E-03; Z-score: 1.19E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.83E-03; Fold-change: 1.77E-01; Z-score: 4.55E-01

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