Abstract PR8: Insensitivity to RAF inhibition by vemurafenib in BRAF mutant colorectal cancer by EGFR-mediated reactivation of MAPK signaling

• Published in: Clinical cancer research 2012-05, Vol.18 (10_Supplement), p.PR8-PR8
• Main Authors: Corcoran, Ryan B., Hung, Kenneth E., Flaherty, Keith T., Piris, Adriano, Wargo, Jennifer A., Settleman, Jeffrey, Mino-Kenudson, Mari, Engelman, Jeffrey A., Ebi, Hiromichi, Turke, Alexa B., Coffee, Erin M., Nishino, Michiya, Cogdill, Alexandria P., Brown, Ronald D., Pelle, Patricia Della, Dias-Santagata, Dora
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.MECHRES-PR8

BRAF mutations occur in 10–15% of colorectal cancers (CRCs) and confer adverse outcome in the metastatic setting. While RAF inhibitors such as vemurafenib (PLX4032) have proven effective in BRAF mutant melanoma (∼60–80% response rates), they are surprisingly ineffective in BRAF mutant CRCs (∼5% response rate), and the reason for this disparity remains unclear. Compared to BRAF mutant melanoma cells, BRAF mutant CRC cells were less sensitive to vemurafenib, and P-ERK suppression was not sustained in response to treatment. Although transient inhibition of phospho-ERK by vemurafenib was observed in CRC, rapid ERK re-activation occurred through EGFR-mediated activation of RAS and CRAF. BRAF mutant CRC cell lines and patient tumor specimens expressed significantly higher levels of phospho-EGFR than BRAF mutant melanoma cell lines and primary tumor specimens, suggesting that CRCs are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of MAPK signaling in BRAF mutant CRC cells and markedly improved efficacy in vitro. In vivo, combined RAF and EGFR inhibition led to sustained suppression of MAPK signaling and to robust tumor regressions in BRAF mutant colorectal xenografts. These findings support evaluation of combined RAF and EGFR inhibition in clinical trials in patients with BRAF mutant CRC. This proffered talk is also presented as Poster B11.