Reference Detail

Ref Type

Journal Article

PMID

(28951457)

Authors

Yaeger R, Yao Z, Hyman DM, Hechtman JF, Vakiani E, Zhao H, Su W, Wang L, Joelson A, Cercek A, Baselga J, de Stanchina E, Saltz L, Berger MF, Solit DB, Rosen N

Title

Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	77	23	2017 12 01	6513-6523	Cancer Res

URL

Abstract Text

BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS-RAF-MEK-ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513-23. ©2017 AACR.

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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 V600E NRAS G13R	colorectal cancer	predicted - sensitive	BGB659 + Cetuximab	Preclinical - Pdx	Actionable	In a preclinical study, BGB659 and Erbitux (cetuximab) combination treatment resulted in sustained inhibition of Mek and Erk phosphorylation, lead to tumor regression in patient-derived xenograft models of colorectal cancer harboring BRAF V600E and NRAS G13R (PMID: 28951457).	28951457
BRAF V600E BRAF amp	colorectal cancer	predicted - resistant	Panitumumab + Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with BRAF V600E colorectal cancer developed progressive disease after a partial response lasting 24 weeks to Vectibix (panitumumab) and Zelboraf (vemurafenib) combination treatment, amplification of BRAF V600E was identified as an acquired alteration at the time of progression (PMID: 28951457).	28951457
BRAF V600E NRAS G13R	colorectal cancer	predicted - resistant	Alpelisib + Cetuximab + Encorafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with BRAF V600E colorectal cancer developed progressive disease after a partial response lasting 24 weeks to Alpelisib (BYL719), Erbitux (cetuximab), and Braftovi (encorafenib) combination treatment, NRAS G13R was identified as an acquired mutation in liver metastasis at the time of progression (PMID: 28951457).	28951457
BRAF V600E NRAS Q61K	colorectal cancer	predicted - resistant	Panitumumab + Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with BRAF V600E colorectal cancer developed progressive disease after a partial response lasting 40 weeks to Vectibix (panitumumab) and Zelboraf (vemurafenib) combination treatment, NRAS Q61K was identified as an acquired mutation at the time of progression (PMID: 28951457).	28951457
BRAF V47_D380del BRAF V600E	colorectal cancer	predicted - resistant	Alpelisib + Cetuximab + Encorafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with BRAF V600E colorectal cancer developed progressive disease after a partial response lasting 24 weeks to Alpelisib (BYL719), Erbitux (cetuximab), and Braftovi (encorafenib) combination treatment, BRAF V47_D380del (reported as deletion of exons 2-8) was identified as an acquired mutation in peritoneal metastasis at the time of progression (PMID: 28951457).	28951457
BRAF V600E NRAS over exp	colorectal cancer	resistant	Cetuximab + Vemurafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, overexpression of wild-type NRAS in colorectal cancer cell lines harboring BRAF V600E induced Ras activation and Braf/Craf dimerization, conferred resistance to Erbitux (cetuximab) and Zelboraf (vemurafenib) combination treatment in culture and in cell line xenograft models (PMID: 28951457).	28951457
BRAF V600E BRAF amp	colorectal cancer	resistant	Cetuximab + Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with BRAF V600E colorectal cancer developed progressive disease after a partial response lasting 16 weeks to Erbitux (cetuximab) and Zelboraf (vemurafenib) combination treatment, amplification of BRAF V600E was identified as an acquired alteration at the time of progression (PMID: 28951457).	28951457
BRAF V600E NRAS over exp	colorectal cancer	sensitive	BGB659 + Cetuximab	Preclinical - Cell culture	Actionable	In a preclinical study, BGB659 and Erbitux (cetuximab) combination treatment demonstrated enhanced inhibition of Erk phosphorylation and growth in BRAF V600E colorectal cancer cell lines overexpressing Nras in culture (PMID: 28951457).	28951457
BRAF V600E NRAS amp	colorectal cancer	predicted - resistant	Panitumumab + Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with BRAF V600E colorectal cancer developed progressive disease after achieving stable disease for 16 weeks with Vectibix (panitumumab) and Zelboraf (vemurafenib) combination treatment, NRAS amplification was identified as an acquired alteration at the time of progression (PMID: 28951457).	28951457