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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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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 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 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 - 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 | 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 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 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 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 |
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 |