Drug Information

Drug (ID: DG00306) and It's Reported Resistant Information

Name	Vemurafenib
Synonyms	PLX4032; RG7204; RO5185426; Zelboraf (TN); Vemurafenib (BRAF inhibitor) Click to Show/Hide
Indication	In total 1 Indication(s) Melanoma [ICD-11: 2C30] Approved [1]
Structure
Drug Resistance Disease(s)	Disease(s) with Clinically Reported Resistance for This Drug (3 diseases) Melanoma [ICD-11: 2C30] [2], [3] Multiple myeloma [ICD-11: 2A83] [4] Thyroid cancer [ICD-11: 2D10] [5] Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases) Melanoma [ICD-11: 2C30] [1]
Target	Serine/threonine-protein kinase B-raf (BRAF)	BRAF_HUMAN	[1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula	C23H18ClF2N3O3S
IsoSMILES	CCCS(=O)(=O)NC1=C(C(=C(C=C1)F)C(=O)C2=CNC3=C2C=C(C=N3)C4=CC=C(C=C4)Cl)F
InChI	1S/C23H18ClF2N3O3S/c1-2-9-33(31,32)29-19-8-7-18(25)20(21(19)26)22(30)17-12-28-23-16(17)10-14(11-27-23)13-3-5-15(24)6-4-13/h3-8,10-12,29H,2,9H2,1H3,(H,27,28)
InChIKey	GPXBXXGIAQBQNI-UHFFFAOYSA-N
PubChem CID	42611257
ChEBI ID	CHEBI:63637
TTD Drug ID	D0Y9EW
VARIDT ID	DR00711
INTEDE ID	DR1677
DrugBank ID	DB08881

Type(s) of Resistant Mechanism of This Drug

ADTT: Aberration of the Drug's Therapeutic Target

EADR: Epigenetic Alteration of DNA, RNA or Protein

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

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Multiple myeloma [ICD-11: 2A83]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)		Click to Show/Hide
Key Molecule: GTPase Nras (NRAS)			[4]
Molecule Alteration	Missense mutation	p.Q61H	Molecule Info
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]		Disease Info
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).
Key Molecule: GTPase Nras (NRAS)			[4]
Molecule Alteration	Missense mutation	p.G13R	Molecule Info
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]		Disease Info
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).
Key Molecule: GTPase Nras (NRAS)			[4]
Molecule Alteration	Missense mutation	p.G12A	Molecule Info
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]		Disease Info
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).

Colorectal cancer [ICD-11: 2B91]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-145				[6]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	COLO205 cells	Colon	Homo sapiens (Human)	CVCL_F402
In Vivo Model	BALB/c nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Established vemurafenib-resistant cell line colo205/V andfound that the miR-145 expression was significantly down-regulated in colo205/V cells compared to normal colo205cells. Moreover, the overexpression of miR-145 could in-crease the sensitivity of colo205/V cells to vemurafenib bothin vitro and in vivo.

Melanoma [ICD-11: 2C30]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Aberration of the Drug's Therapeutic Target (ADTT)			Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF)				[3]
Molecule Alteration	Structural variation		Copy number gain	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)			Click to Show/Hide
Key Molecule: hsa-miR-204-5p				[1]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ERK1/2/MEK activation signaling pathway\|hsa04210)		Regulation
	MAPK signaling pathway		Activation	hsa04010
	PI3K signaling pathway		Activation	hsa04151
	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				[1]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ERK1/2/MEK activation signaling pathway\|hsa04210)		Regulation
	MAPK signaling pathway		Activation	hsa04010
	PI3K signaling pathway		Activation	hsa04151
	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)			Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF)				[1]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ERK1/2/MEK activation signaling pathway\|hsa04210)		Regulation
	MAPK signaling pathway		Activation	hsa04010
	PI3K signaling pathway		Activation	hsa04151
	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)				[7]
Molecule Alteration	Missense mutation		p.Q61H	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	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)				[7]
Molecule Alteration	Missense mutation		p.G12R	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	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)				[7]
Molecule Alteration	Missense mutation		p.G12C	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	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]
Molecule Alteration	Missense mutation		p.Q61H	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[9]
Molecule Alteration	Missense mutation		p.F57C	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[8]
Molecule Alteration	Missense mutation		p.V35M	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[8]
Molecule Alteration	Missense mutation		p.C125S	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[10]
Molecule Alteration	Missense mutation		p.E545K	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[11]
Molecule Alteration	Missense mutation		p.R159S	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[7], [8], [12]
Molecule Alteration	Missense mutation		p.Q61R	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	PI3K/AKT/PTEN signaling pathway		Inhibition	hsa04151
In Vitro Model	M229 cells	Skin	Homo sapiens (Human)	CVCL_D748
	M238 cells	Skin	Homo sapiens (Human)	CVCL_D751
	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)				[7]
Molecule Alteration	Missense mutation		p.Q61L	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	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)				[7], [8], [12]
Molecule Alteration	Missense mutation		p.Q61K	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	PI3K/AKT/PTEN signaling pathway		Inhibition	hsa04151
In Vitro Model	M229 cells	Skin	Homo sapiens (Human)	CVCL_D748
	M238 cells	Skin	Homo sapiens (Human)	CVCL_D751
	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)				[7]
Molecule Alteration	Missense mutation		p.G13R	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	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)				[7]
Molecule Alteration	Missense mutation		p.G12R	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	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)				[7]
Molecule Alteration	Missense mutation		p.G12D	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
	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)				[2], [3]
Molecule Alteration	Missense mutation		p.Q61K	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[13]
Molecule Alteration	Missense mutation		p.Q61K	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[13]
Molecule Alteration	Missense mutation		p.Q61K	Molecule Info
Resistant Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)			Click to Show/Hide
Key Molecule: Autophagy protein 5 (ATG5)				[14]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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
	A375-R cells	Skin	Homo sapiens (Human)	CVCL_6234
	G-361 cells	Skin	Homo sapiens (Human)	CVCL_1220
	G361/R cells	Skin	Homo sapiens (Human)	CVCL_IW13
	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)				[14]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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
	A375-R cells	Skin	Homo sapiens (Human)	CVCL_6234
	G-361 cells	Skin	Homo sapiens (Human)	CVCL_1220
	G361/R cells	Skin	Homo sapiens (Human)	CVCL_IW13
	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				[14]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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
	A375-R cells	Skin	Homo sapiens (Human)	CVCL_6234
	G-361 cells	Skin	Homo sapiens (Human)	CVCL_1220
	G361/R cells	Skin	Homo sapiens (Human)	CVCL_IW13
	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)				[14]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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
	A375-R cells	Skin	Homo sapiens (Human)	CVCL_6234
	G-361 cells	Skin	Homo sapiens (Human)	CVCL_1220
	G361/R cells	Skin	Homo sapiens (Human)	CVCL_IW13
	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				[15]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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				[16]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	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				[16]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	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				[16]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	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)			Click to Show/Hide
Key Molecule: RAF proto-oncogene serine/threonine-protein kinase (RAF1)				[15]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[15]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[15]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
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)				[16]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Disease	Melanoma [ICD-11: 2C30.0]			Disease Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	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.

Thyroid cancer [ICD-11: 2D10]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Aberration of the Drug's Therapeutic Target (ADTT)			Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF)				[5]
Molecule Alteration	Missense mutation		p.V600E	Molecule Info
Resistant Disease	Papillary thyroid carcinoma [ICD-11: 2D10.1]			Disease Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Low throughput experiment assay
Mechanism Description	BRAFV600E is the most common mutation in PTC, occurring in about 60% of PTC tumors, and has been described as a clonal event since it occurs in the majority of tumor cells. BRAFV600E PTC exhibits primary resistance to RAI treatment, higher rates of tumor recurrence and metastases, and lower survival rates. Remarkably, the BRAFV600E mutation not only promotes thyroid tumor cell proliferation, adhesion, migration and invasion, but also up-regulates epigenetic pathways that silence expression of the sodium/iodide symporter. This blocks iodide uptake, which may be one cause of primary resistance to RAI. Present in other cancers, including 40-70% of malignant melanomas and 10% of colorectal cancers, BRAFV600E positive tumors provide one important case study for the evolution of drug resistance.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Mitogen-activated protein kinase 3 (MAPK3)				[17]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Disease	Papillary thyroid carcinoma [ICD-11: 2D10.1]			Disease Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	ERK signaling pathway		Activation	hsa04210
	mTOR signaling pathway		Activation	hsa04150
In Vitro Model	BCPAP cells	Thyroid	Homo sapiens (Human)	CVCL_0153
Experiment for Molecule Alteration	Western blotting assay
Experiment for Drug Resistance	Alamar blue assay
Mechanism Description	Resistance to vemurafenib in BCPAP appeared to be mediated by constitutive overexpression of phospho-ERK and by resistance to inhibition of both phospho-mTOR and phospho-S6 ribosomal protein after vemurafenib treatment.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)				[5]
Molecule Alteration	Structural variation		Copy number gain	Molecule Info
Resistant Disease	Papillary thyroid carcinoma [ICD-11: 2D10.1]			Disease Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Low throughput experiment assay
Mechanism Description	We found that MCL1 (myeloid cell leukemia 1, chromosome 1q) copy number gain is associated with resistance to vemurafenib treatment in metastatic BRAF V600E-PTC cells. MCL1, an anti-apoptotic member of the BCL2 family, is amplified in many cancers and plays a crucial role in tumor progression and metastasis, and likely in drug resistance.

References

Ref 1	miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma. Cancer Res. 2018 Feb 15;78(4):1017-1030. doi: 10.1158/0008-5472.CAN-17-1318. Epub 2017 Dec 11.
Ref 2	COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010 Dec 16;468(7326):968-72. doi: 10.1038/nature09627. Epub 2010 Nov 24.
Ref 3	Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
Ref 4	Spatially divergent clonal evolution in multiple myeloma: overcoming resistance to BRAF inhibition. Blood. 2016 Apr 28;127(17):2155-7. doi: 10.1182/blood-2015-12-686782. Epub 2016 Feb 16.
Ref 5	Evolution of resistance to thyroid cancer therapy. Aging (Albany NY). 2016 Aug;8(8):1576-7. doi: 10.18632/aging.101030.
Ref 6	Overexpression of miR-145 increases the sensitivity of vemurafenib in drug-resistant colo205 cell line. Tumour Biol. 2014 Apr;35(4):2983-8. doi: 10.1007/s13277-013-1383-x. Epub 2013 Nov 19.
Ref 7	Tumor heterogeneity and plasticity as elusive drivers for resistance to MAPK pathway inhibition in melanoma. Oncogene. 2015 Jun 4;34(23):2951-7. doi: 10.1038/onc.2014.249. Epub 2014 Aug 11.
Ref 8	The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014 Jan;4(1):94-109. doi: 10.1158/2159-8290.CD-13-0617. Epub 2013 Nov 21.
Ref 9	BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014 Apr 1;20(7):1965-77. doi: 10.1158/1078-0432.CCR-13-3122. Epub 2014 Jan 24.
Ref 10	Detailed imaging and genetic analysis reveal a secondary BRAF(L505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell Melanoma Res. 2015 May;28(3):318-23. doi: 10.1111/pcmr.12347. Epub 2015 Jan 7.
Ref 11	Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. J Clin Invest. 2015 Apr;125(4):1459-70. doi: 10.1172/JCI78954. Epub 2015 Feb 23.
Ref 12	Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010 Dec 16;468(7326):973-7. doi: 10.1038/nature09626. Epub 2010 Nov 24.
Ref 13	The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma .Expert Opin Drug Discov. 2016 Sep;11(9):907-16. doi: 10.1080/17460441.2016.1201057. Epub 2016 Jun 23. 10.1080/17460441.2016.1201057
Ref 14	miR-216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. Cell Signal. 2018 Jan;42:30-43. doi: 10.1016/j.cellsig.2017.09.024. Epub 2017 Oct 2.
Ref 15	miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways. Oncotarget. 2016 Aug 16;7(33):53558-53570. doi: 10.18632/oncotarget.10669.
Ref 16	Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b. Oncotarget. 2016 Jan 26;7(4):4428-41. doi: 10.18632/oncotarget.6599.
Ref 17	Hyperactive ERK and persistent mTOR signaling characterize vemurafenib resistance in papillary thyroid cancer cells .Oncotarget. 2016 Feb 23;7(8):8676-87. doi: 10.18632/oncotarget.6779. 10.18632/oncotarget.6779

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Prof. Feng ZHU (zhufeng@zju.edu.cn)