Title |
EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib
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Published in |
Cancer Discovery, March 2012
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DOI | 10.1158/2159-8290.cd-11-0341 |
Pubmed ID | |
Authors |
Ryan B. Corcoran, Hiromichi Ebi, Alexa B. Turke, Erin M. Coffee, Michiya Nishino, Alexandria P. Cogdill, Ronald D. Brown, Patricia Della Pelle, Dora Dias-Santagata, Kenneth E. Hung, Keith T. Flaherty, Adriano Piris, Jennifer A. Wargo, Jeffrey Settleman, Mari Mino-Kenudson, Jeffrey A. Engelman |
Abstract |
BRAF mutations occur in 10-15% of colorectal cancers (CRCs) and confer adverse outcome. While RAF inhibitors such as vemurafenib (PLX4032) have proven effective in BRAF mutant melanoma, they are surprisingly ineffective in BRAF mutant CRCs, 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 CRCs expressed higher levels of phospho-EGFR than BRAF mutant melanomas, 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 and in vivo. These findings support evaluation of combined RAF and EGFR inhibition in BRAF mutant CRC patients. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 4 | 57% |
Austria | 1 | 14% |
Unknown | 2 | 29% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 5 | 71% |
Science communicators (journalists, bloggers, editors) | 1 | 14% |
Members of the public | 1 | 14% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Germany | 2 | <1% |
United Kingdom | 2 | <1% |
Netherlands | 1 | <1% |
Italy | 1 | <1% |
Korea, Republic of | 1 | <1% |
Spain | 1 | <1% |
United States | 1 | <1% |
Unknown | 505 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 113 | 22% |
Student > Ph. D. Student | 108 | 21% |
Student > Master | 42 | 8% |
Student > Bachelor | 40 | 8% |
Student > Doctoral Student | 30 | 6% |
Other | 87 | 17% |
Unknown | 94 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 135 | 26% |
Biochemistry, Genetics and Molecular Biology | 114 | 22% |
Medicine and Dentistry | 107 | 21% |
Pharmacology, Toxicology and Pharmaceutical Science | 14 | 3% |
Chemistry | 9 | 2% |
Other | 31 | 6% |
Unknown | 104 | 20% |