EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib

By R. Corcoran, H. Ebi, Alexa B. Turke, Erin M. Coffee, Michiya Nishino, Alexandria P. Cogdill, Ronald D. Brown, P. Della Pelle, D. Dias-Santagata, K. Hung and 6 more. Cancer Discovery, 2012

944 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5ef58b9e7dec3e8e77bf11999b6ae8a7bb74e258

How researchers see this paper

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In Molecular Biology

1. Carlos L. Arteaga
2. Myles A. Brown
3. X. S. Liu
4. Michael I. Love
5. Wei Li
6. R. Salazar
7. A. Bardelli
8. Jun S. Liu

In Oncology

1. Carlos L. Arteaga
2. Fortunato Ciardiello
3. D. Hicklin
4. J. Engelman

Citations in the corpus

• Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. (2019, neutral): “Abdominal pain 65 (29) 13 (6) 49 (23) 5 (2) 48 (25) 9 (5)”
• MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens (2014, background): “colorectal cancer cells with the BRAF V600 mutation [15,29].”
• ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. (2016, background): “Feedback reactivation of EGFR in CRC could explain why CRCs generally have a lower response to BRAF inhibitors [37, 71].”
• Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. (2013, background): “It certain contexts, it has been demonstrated that RAF inhibitor efficacy can be limited by ERK reactivation that occurs within 24 hours (22).”