A critical step towards defining tailored therapy in cancer patients 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 knock-in 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 towards 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, since 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.

BRAF V600E is a determinant of sensitivity to proteasome inhibitors.

ZECCHIN, Davide;BOSCARO, Valentina;MEDICO, Enzo;BARAULT, LUDOVIC;MARTINI, MIriam;ARENA, Sabrina;BARDELLI, Alberto;GALLICCHIO, Margherita;DI NICOLANTONIO, Federica
2013

Abstract

A critical step towards defining tailored therapy in cancer patients 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 knock-in 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 towards 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, since 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.
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http://mct.aacrjournals.org/content/early/2013/10/09/1535-7163.MCT-13-0243.abstract
BRAF; Proteasome inhibitors; cancer mutations; EGFR; Bortezomib; Pharmacogenomics
Zecchin D;Boscaro V;Medico E;Barault L;Martini M;Arena S;Cancelliere C;Bartolini A;Crowley EH;Bardelli A;Gallicchio M;Di Nicolantonio F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/140935
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