Data from Clinical Acquired Resistance to RAF Inhibitor Combinations in <i>BRAF</i>-Mutant Colorectal Cancer through MAPK Pathway Alterations

Abstract

<div>Abstract<p><i>BRAF</i> mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in <i>BRAF</i>-mutant melanoma, response rates in <i>BRAF</i>-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with <i>BRAF</i>-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including <i>KRAS</i> amplification, <i>BRAF</i> amplification, and a <i>MEK1</i> mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in <i>BRAF</i>-mutant colorectal cancer and suggests therapeutic options to overcome resistance.</p><p><b>Significance:</b> RAF inhibitor combinations represent promising approaches in clinical development for <i>BRAF</i>-mutant colorectal cancer. Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling, highlighting the critical dependence of <i>BRAF</i>-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance. <i>Cancer Discov; 5(4); 358–67. ©2015 AACR</i>.</p><p><i>See related commentary by Meador and Pao, p. 348</i></p><p>This article is highlighted in the In This Issue feature, p. 333</p></div>