High-throughput simultaneous screen and counterscreen identifies homoharringtonine as synthetic lethal with von Hippel-Lindau loss in renal cell carcinoma.

摘要: Renal cell carcinoma (RCC) accounts for 85% of primary renal neoplasms, and is rarely curable when metastatic. Approximately 70% RCCs are clear-cell type (ccRCC), in >80% the von Hippel-Lindau (VHL) gene mutated or silenced. We developed a novel, high-content, screening strategy identification small molecules that synthetic lethal with genes cancer. In this strategy, screen counterscreen conducted simultaneously by differentially labeling mutant reconstituted isogenic tumor line pairs different fluorochromes using highly sensitive high-throughput imaging-based platform. This approach minimizes confounding factors from sequential screening, more accurately replicates vivo cancer setting where cells adjacent to normal cells. A ~12,800 identified homoharringtonine (HHT), an FDA-approved drug treating chronic myeloid leukemia, as VHL-synthetic agent ccRCC. HHT induced apoptosis VHL-mutant, but not VHL-reconstituted, ccRCC cells, inhibited growth 30% VHL-mutant patient-derived tumorgraft lines tested. Building on novel utilizing validated RCC model recapitulating genetics responsiveness human RCC, these studies identify potential therapeutic subset VHL-deficient ccRCCs.