Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations.

Cancer Discov
Authors
Keywords
Abstract

UNLABELLED: BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-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 BRAF-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 KRAS amplification, BRAF amplification, and a MEK1 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 BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.

SIGNIFICANCE: RAF inhibitor combinations represent promising approaches in clinical development for BRAF-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 BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance.

Year of Publication
2015
Journal
Cancer Discov
Volume
5
Issue
4
Pages
358-67
Date Published
2015 Apr
ISSN
2159-8290
URL
DOI
10.1158/2159-8290.CD-14-1518
PubMed ID
25673644
PubMed Central ID
PMC4390490
Links
Grant list
U54 HG003067 / HG / NHGRI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
1K08CA166510 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
K08 CA166510 / CA / NCI NIH HHS / United States