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- W4362478523 abstract "<div>Abstract<p>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 <i>PTEN</i> or <i>RB1</i> were silenced in combination with the targeted knockin of cancer-associated mutations in <i>EGFR, KRAS, BRAF</i>, or <i>PIK3CA</i> 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 <i>BRAF</i> V600E–mutant cells, irrespective of PTEN or RB1 expression. Preferential targeting of <i>BRAF</i>-mutant cells by proteasome inhibitors was corroborated in a second <i>BRAF V600E</i> 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 <i>in vivo</i> activity in a <i>BRAF</i>-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 <i>BRAF</i>-mutant colorectal cancer cells. Our findings indicated that proteasome inhibition might represent a valuable targeting strategy in <i>BRAF</i> V600E–mutant colorectal tumors. <i>Mol Cancer Ther; 12(12); 2950–61. ©2013 AACR</i>.</p></div>" @default.
- W4362478523 created "2023-04-05" @default.
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- W4362478523 date "2023-04-03" @default.
- W4362478523 modified "2023-09-30" @default.
- W4362478523 title "Data from <i>BRAF</i> V600E Is a Determinant of Sensitivity to Proteasome Inhibitors" @default.
- W4362478523 doi "https://doi.org/10.1158/1535-7163.c.6535635.v1" @default.
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