BRAF V600E Is a Determinant of Sensitivity to Proteasome Inhibitors
| Autor: | Federica Di Nicolantonio, Alberto Bardelli, Enzo Medico, Davide Zecchin, Sabrina Arena, Margherita Gallicchio, Miriam Martini, Alice Bartolini, Valentina Boscaro, Carlotta Cancelliere, Emily Crowley, Ludovic Barault |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Indoles Colorectal cancer medicine.disease_cause Bortezomib chemistry.chemical_compound 0302 clinical medicine Cluster Analysis Telomerase Sulfonamides 0303 health sciences biology BRAF Proteasome inhibitors cancer mutations EGFR Pharmacogenomics 3. Good health Oncology 030220 oncology & carcinogenesis Female KRAS Signal Transduction medicine.drug Proto-Oncogene Proteins B-raf Genotype Antineoplastic Agents 03 medical and health sciences Cell Line Tumor Biomarkers Tumor medicine Humans PTEN neoplasms 030304 developmental biology Cancer medicine.disease Xenograft Model Antitumor Assays Carfilzomib digestive system diseases 14-3-3 Proteins Proteasome chemistry Drug Resistance Neoplasm Exoribonucleases Mutation biology.protein Proteasome inhibitor Cancer research Drug Screening Assays Antitumor |
| Zdroj: | Molecular Cancer Therapeutics; Vol 12 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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. Mol Cancer Ther; 12(12); 2950–61. ©2013 AACR. |
| Databáze: | OpenAIRE |
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