Abstract

Discovering chemosensitivity pathways or nodes is an attractive strategy for formulating new drug combinations for cancer. Microtubules are among the most successful anticancer drugs targets. Therefore, we implemented a small interfering RNA (siRNA) synthetic lethal screen targeting 5,520 unique druggable genes to identify novel chemosensitivity nodes for vinblastine, a clinically used microtubule destabilizing agent. We transiently transfected human glioblastoma cells with siRNAs for 48 h and then treated cells with a sub-lethal concentration of vinblastine. Forty-eight h later, we analyzed cell viability and, using a series of statistical methods, identified 65 gene products that, when suppressed, sensitized glioblastoma cells to vinblastine. After completion of the secondary assays, we focused on one siRNA, BCL-xL, because of its role in the intrinsic apoptosis signaling pathway, as well as the availability of pharmacological inhibitors. We found nontoxic concentrations of ABT-263, an inhibitor of the BCL-2 family members (BCL-2, BCL-xL, and BCL-w), sensitized glioblastoma and non-small-cell lung cancer cells to vinblastine and induced apoptosis through the intrinsic cell death pathway. These results illustrate the usefulness of unbiased siRNA screens as a method for identifying potential novel anticancer therapeutic combinations.