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Ref Type Journal Article
PMID (27523909)
Authors Karoulia Z, Wu Y, Ahmed TA, Xin Q, Bollard J, Krepler C, Wu X, Zhang C, Bollag G, Herlyn M, Fagin JA, Lujambio A, Gavathiotis E, Poulikakos PI
Title An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling.
Journal Vol Issue Date Pages Journal Short Title
Cancer cell 30 3 2016 Sep 12 485-498 Cancer Cell
URL
Abstract Text The complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. Here we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the αC helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex. The biochemical effect of RAF inhibitor in cells is the combined outcome of the two mechanisms. Therapeutic strategies including αC-helix-IN inhibitors are more effective in multiple mutant BRAF-driven tumor models, including colorectal and thyroid BRAF(V600E) cancers, in which first-generation RAF inhibitors have been ineffective.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600D melanoma sensitive AZ628 Preclinical - Cell culture Actionable In a preclinical study, AZ628 inhibited proliferation of melanoma cell lines harboring BRAF V600D in culture (PMID: 27523909). 27523909
BRAF V600D melanoma sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of melanoma cell lines harboring BRAF V600D in culture (PMID: 27523909). 27523909
BRAF L597V NRAS Q61K lung non-small cell carcinoma sensitive AZ628 Preclinical - Cell culture Actionable In a preclinical study, AZ628 inhibited proliferation of non-small cell lung cancer cells harboring both BRAF L597V and NRAS Q61K in culture (PMID: 27523909). 27523909
BRAF V600E colorectal cancer sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of colorectal cancer cells harboring BRAF V600E in culture (PMID: 27523909). 27523909
BRAF L597V NRAS Q61K lung non-small cell carcinoma decreased response PLX7904 Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells harboring both BRAF L597V and NRAS Q61K demonstrated decreased sensitivity to PLX7904 in culture (PMID: 27523909). 27523909
BRAF D594G NRAS G12D melanoma decreased response PLX7904 Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to PLX7904 in culture (PMID: 27523909). 27523909
BRAF D594G NRAS G12D melanoma sensitive AZ628 Preclinical - Cell culture Actionable In a preclinical study, AZ628 inhibited proliferation of melanoma cell lines harboring both BRAF D594G and NRAS G12D in culture (PMID: 27523909). 27523909
BRAF G466E melanoma decreased response Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF G466E demonstrated decreased sensitivity to Zelboraf (vemurafenib) in culture (PMID: 27523909). 27523909
BRAF V600E melanoma sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of melanoma cell lines harboring either monomeric BRAF V600E or dimeric isoform of V600E which conferred Zelboraf (vemurafenib)-resistance in culture (PMID: 27523909). 27523909
BRAF V600E thyroid cancer conflicting Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, thyroid cancer cells harboring BRAF V600E demonstrated decreased sensitivity to Zelboraf (vemurafenib) in culture (PMID: 27523909). 27523909
BRAF V600E melanoma sensitive SB590885 Preclinical - Cell culture Actionable In a preclinical study, SB590885 inhibited proliferation of melanoma cell lines harboring either monomeric BRAF V600E or dimeric isoform of V600E which conferred Zelboraf (vemurafenib)-resistance in culture (PMID: 27523909). 27523909
BRAF D594G NRAS G12D melanoma sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of melanoma cell lines harboring both BRAF D594G and NRAS G12D in culture (PMID: 27523909). 27523909
BRAF D594G NRAS G12D melanoma decreased response Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to Zelboraf (vemurafenib) in culture (PMID: 27523909). 27523909
BRAF V600D melanoma sensitive PLX7904 Preclinical - Cell culture Actionable In a preclinical study, PLX7904 inhibited proliferation of melanoma cell lines harboring BRAF V600D in culture (PMID: 27523909). 27523909
BRAF G466V lung non-small cell carcinoma no benefit Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells harboring BRAF G466V demonstrated decreased sensitivity to Zelboraf (vemurafenib) in culture (PMID: 27523909). 27523909
BRAF L597V NRAS Q61K lung non-small cell carcinoma decreased response Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells harboring both BRAF L597V and NRAS Q61K demonstrated decreased sensitivity to Zelboraf (vemurafenib) in culture (PMID: 27523909). 27523909
BRAF L597V NRAS Q61K lung non-small cell carcinoma sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of non-small cell lung cancer cells harboring both BRAF L597V and NRAS Q61K in culture (PMID: 27523909). 27523909
BRAF V600R melanoma sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of melanoma cell lines harboring BRAF V600R in culture (PMID: 27523909). 27523909
BRAF wild-type NRAS wild-type melanoma resistant PLX7904 Preclinical - Cell culture Actionable In a preclinical study, BRAF and NRAS wild-type melanoma cells were resistant to PLX7904 in culture (PMID: 27523909). 27523909
BRAF G466E melanoma sensitive AZ628 Preclinical - Cell culture Actionable In a preclinical study, AZ628 inhibited proliferation of melanoma cell lines harboring BRAF G466E in culture (PMID: 27523909). 27523909
BRAF G466V lung non-small cell carcinoma sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of non-small cell lung cancer cells harboring BRAF G466V in culture (PMID: 27523909). 27523909
BRAF wild-type NRAS wild-type melanoma sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of BRAF and NRAS wild-type melanoma cells in culture (PMID: 27523909). 27523909
BRAF V600R melanoma sensitive PLX7904 Preclinical - Cell culture Actionable In a preclinical study, PLX7904 inhibited proliferation of melanoma cells harboring BRAF V600R in culture (PMID: 27523909). 27523909
BRAF wild-type NRAS wild-type melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, BRAF and NRAS wild-type melanoma cells were resistant to Zelboraf (vemurafenib) in culture (PMID: 27523909). 27523909
BRAF V600R melanoma sensitive AZ628 Preclinical - Cell culture Actionable In a preclinical study, AZ628 inhibited proliferation of melanoma cell lines harboring BRAF V600R in culture (PMID: 27523909). 27523909
BRAF V600D melanoma sensitive Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) inhibited proliferation of melanoma cells harboring BRAF V600D in culture (PMID: 27523909). 27523909
BRAF V600E melanoma sensitive AZ628 Preclinical - Cell culture Actionable In a preclinical study, AZ628 inhibited proliferation of melanoma cell lines harboring either monomeric BRAF V600E or dimeric isoform of V600E which conferred Zelboraf (vemurafenib)-resistance in culture (PMID: 27523909). 27523909
BRAF V600D melanoma sensitive Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, Tafinlar (dabrafenib) inhibited proliferation of melanoma cells harboring BRAF V600D in culture (PMID: 27523909). 27523909
BRAF V600E thyroid cancer sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of thyroid cancer cells harboring BRAF V600E in culture (PMID: 27523909). 27523909
BRAF D594G NRAS G12D melanoma decreased response Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to Tafinlar (dabrafenib) in culture (PMID: 27523909). 27523909
BRAF wild-type NRAS wild-type melanoma sensitive AZ628 Preclinical - Cell culture Actionable In a preclinical study, AZ628 inhibited proliferation of BRAF and NRAS wild-type melanoma cells in culture (PMID: 27523909). 27523909
BRAF V600E colorectal cancer sensitive PLX4720 + TAK-632 Preclinical - Cell line xenograft Actionable In a preclinical study, PLX4720 and TAK-632 combination treatment resulted in durable inhibition of Erk signaling and tumor growth in xenograft models of colorectal cancer cells harboring BRAF V600E (PMID: 27523909). 27523909
BRAF V600R melanoma sensitive Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, Tafinlar (dabrafenib) inhibited proliferation of melanoma cells harboring BRAF V600R in culture (PMID: 27523909). 27523909
BRAF G466E melanoma decreased response PLX7904 Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF G466E demonstrated decreased sensitivity to PLX7904 in culture (PMID: 27523909). 27523909
BRAF G466E melanoma decreased response Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF G466E demonstrated decreased sensitivity to Tafinlar (dabrafenib) in culture (PMID: 27523909). 27523909
BRAF V600R melanoma sensitive Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) inhibited proliferation of melanoma cells harboring BRAF V600R in culture (PMID: 27523909). 27523909
BRAF G466E melanoma sensitive TAK-632 Preclinical - Cell culture Actionable In a preclinical study, TAK-632 inhibited proliferation of melanoma cell lines harboring BRAF G466E in culture (PMID: 27523909). 27523909
BRAF L597V NRAS Q61K lung non-small cell carcinoma decreased response Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells harboring both BRAF L597V and NRAS Q61K demonstrated decreased sensitivity to Tafinlar (dabrafenib) in culture (PMID: 27523909). 27523909