Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAFV600E colorectal cancer

Erin M. Coffee, Anthony C. Faber, Jatin Roper, Mark J. Sinnamon, Gautam Goel, Lily Keung, Wei Vivian Wang, Loredana Vecchione, Veerle De Vriendt, Barbara J. Weinstein, Roderick T. Bronson, Sabine Tejpar, Ramnik J. Xavier, Jeffrey A. Engelman, Eric S. Martin, Kenneth E. Hung

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Purpose: BRAFV600E mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Although selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAFV600E CRC. Experimental Design: We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAF V600E CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAFV600E CRC. Results: Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAF V600E GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression. Conclusions: We have established a novel GEMM to interrogate BRAFV600E CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials.

Original languageEnglish
Pages (from-to)2688-2698
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number10
DOIs
StatePublished - 15 May 2013
Externally publishedYes

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