Microtubule-destabilizing agents are among the most successful anticancer therapies; however, resistance remains a serious clinical problem in a variety of cancers. There exists a clinical need to develop novel combination therapies to minimize clinical resistance to microtubule-destabilizing agents. Kitchens et al. investigated the use of synthetic lethal small interfering RNA (siRNA) library screening to identify chemosensitivity pathways or nodes to enhance the therapeutic potential of established anticancer agents. A high-throughput siRNA screen targeting the “druggable” genome was evaluated in glioblastoma (GBM) cells in combination with vinblastine (VBL). Sixty-five gene products were toxic to cancer cells in combination with VBL. Of these 65, the prosurvival B-cell lymphoma-extra large (Bcl-xL) siRNA sensitized GBM cells to VBL. The antisense therapeutic targeting B-cell lymphoma 2 (Bcl-2), oblimersen, and the Bcl-2 family inhibitor ABT-283 (navitoclax) mimicked the effects of the Bcl-xL siRNA in GBM and non–small-cell lung cancer cells. This study illustrates how siRNA high-throughput screens can be an efficient, unbiased method to identify novel combination anticancer treatments and thereby potentially increase the efficacy of established anticancer drugs such as VBL.
See article at J Pharmacol Exp Ther 2011, 339:851–858.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics