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

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          Abstract

          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.

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          Author and article information

          Journal
          Cancer Discov
          Cancer discovery
          American Association for Cancer Research (AACR)
          2159-8290
          2159-8274
          Apr 2015
          : 5
          : 4
          Affiliations
          [1 ] Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
          [2 ] Dana Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
          [3 ] Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
          [4 ] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
          [5 ] Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
          [6 ] Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
          [7 ] Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. rbcorcoran@partners.org.
          Article
          2159-8290.CD-14-1518 NIHMS662886
          10.1158/2159-8290.CD-14-1518
          4390490
          25673644
          e4bd1cb3-0dc4-4c25-8acd-f6a33e3c3b62
          ©2015 American Association for Cancer Research.

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