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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 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 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 | 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 | 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 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 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 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 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 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 | 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 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 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 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 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 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 | 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 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 |
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 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 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 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 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 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 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 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 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 | 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 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 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 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 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 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 | 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 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 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 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 |
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