title: EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Turke
authors.forename: Erin M
authors.initials: EM
authors.lastname: Coffee
authors.forename: Michiya
authors.initials: M
authors.lastname: Nishino
authors.forename: Alexandria P
authors.initials: AP
authors.lastname: Cogdill
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Brown
authors.forename: Patricia
authors.initials: P
authors.lastname: Della Pelle
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hung
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Adriano
authors.initials: A
authors.lastname: Piris
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases