EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib

RB Corcoran, H Ebi, AB Turke, EM Coffee, M Nishino… - Cancer discovery, 2012 - AACR
RB Corcoran, H Ebi, AB Turke, EM Coffee, M Nishino, AP Cogdill, RD Brown, P Della Pelle…
Cancer discovery, 2012AACR
BRAF mutations occur in 10% to 15% of colorectal cancers and confer adverse outcome in
the metastatic setting. Although RAF inhibitors such as vemurafenib (PLX4032) have proven
effective in the treatment of BRAF-mutant melanoma, they are surprisingly ineffective in
BRAF-mutant colorectal cancers, and the reason for this disparity remains unclear.
Compared with BRAF-mutant melanoma cells, BRAF-mutant colorectal cancer cells were
less sensitive to vemurafenib, and phospho-extracellular signal-regulated kinase (P-ERK) …
Abstract
BRAF mutations occur in 10% to 15% of colorectal cancers and confer adverse outcome in the metastatic setting. Although RAF inhibitors such as vemurafenib (PLX4032) have proven effective in the treatment of BRAF-mutant melanoma, they are surprisingly ineffective in BRAF-mutant colorectal cancers, and the reason for this disparity remains unclear. Compared with BRAF-mutant melanoma cells, BRAF-mutant colorectal cancer cells were less sensitive to vemurafenib, and phospho-extracellular signal-regulated kinase (P-ERK) suppression was not sustained in response to treatment. Although transient inhibition of P-ERK by vemurafenib was observed in colorectal cancer, rapid ERK reactivation occurred through epidermal growth factor receptor (EGFR)-mediated activation of RAS and CRAF. BRAF-mutant colorectal cancers expressed greater levels of phospho-EGFR than BRAF-mutant melanomas, suggesting that colorectal cancers are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of mitogen-activated protein kinase (MAPK) signaling in BRAF-mutant colorectal cancer cells and markedly improved efficacy in vitro and in vivo. These findings support the evaluation of combined RAF and EGFR inhibition in patients with BRAF-mutant colorectal cancer.
Significance:BRAF valine 600 (V600) mutations occur in 10% to 15% of colorectal cancers, yet these tumors show a surprisingly low clinical response rate (∼5%) to selective RAF inhibitors such as vemurafenib, which have produced dramatic response rates (60%–80%) in melanomas harboring the identical BRAF V600 mutation. We found that EGFR-mediated MAPK pathway reactivation leads to resistance to vemurafenib in BRAF-mutant colorectal cancers and that combined RAF and EGFR inhibition can lead to sustained MAPK pathway suppression and improved efficacy in vitro and in tumor xenografts. Cancer Discovery; 2(3); 227–35. ©2012 AACR.
This article is highlighted in the In This Issue feature, p. 193
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