BRAF V600E is a determinant of sensitivity to proteasome inhibitors

Davide Zecchin, Valentina Boscaro, Enzo Medico, Ludovic Barault, Miriam Martini, Sabrina Arena, Carlotta Cancelliere, Alice Bartolini, Emily H. Crowley, Alberto Bardelli, Margherita Gallicchio, Federica Di Nicolantonio

Research output: Contribution to journalArticle

Abstract

A critical step toward defining tailored therapy in patients with cancer is the identification of genetic interactions that may impair-or boost-the efficacy of selected therapeutic approaches. Cell models able to recapitulate combinations of genetic aberrations are important to find drug-genotype interactions poorly affected by the heterogeneous genetics of human tumors. In order to identify novel pharmacogenomic relationships, we employed an isogenic cell panel that reconstructs cancer genetic scenarios. We screened a library of 43 compounds in human hTERT-HME1 epithelial cells in which PTEN or RB1 were silenced in combination with the targeted knockin of cancer-associated mutations in EGFR, KRAS, BRAF, or PIK3CA oncogenes. Statistical analysis and clustering algorithms were applied to display similar drug response profiles and mutation-specific patterns of activity. From the screen, we discovered that proteasome inhibitors show selectivity toward BRAF V600E-mutant cells, irrespective of PTEN or RB1 expression. Preferential targeting of BRAF-mutant cells by proteasome inhibitors was corroborated in a second BRAF V600E isogenic model, as well as in a panel of colorectal cancer cell lines by the use of the proteasome inhibitor carfilzomib. Notably, carfilzomib also showed striking in vivo activity in a BRAF-mutant human colorectal cancer xenograft model. Vulnerability to proteasome inhibitors is dependent on persistent BRAF signaling, because BRAF V600E blockade by PLX4720 reversed sensitivity to carfilzomib in BRAF-mutant colorectal cancer cells. Our findings indicated that proteasome inhibition might represent a valuable targeting strategy in BRAF V600E-mutant colorectal tumors.

Original languageEnglish
Pages (from-to)2950-2961
Number of pages12
JournalMolecular Cancer Therapeutics
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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