Identification of novel chemosensitivity nodes for vinblastine using siRNA synthetic lethal screens

To identify novel chemosensitivity nodes for vinblastine, a clinically used microtubule destabilizing agent, we implemented a short interfering RNA synthetic lethal screen targeting 5,520 unique druggable genes in T98G glioblastoma cells. We transiently transfected cells with targeting siRNAs for 48 hours then treated with a sub‐lethal concentration of vinblastine. After 48 hours of drug treatment, we analyzed cell viability and identified gene products that sensitized T98G cells to vinblastine. We employed a series of orthogonal statistical methods that identified 65 gene products as sensitizers of T98G cells to vinblastine. We performed a secondary screen which confirmed 35 of the initial 65 genes. As indicated by the primary and secondary screens, we found that with BCL‐xL siRNA, we could sensitize T98G cells to vinblastine. In translating from the siRNA to the BCL‐2 family (BCL‐2, BCL‐xL, and BCL‐w) specific inhibitor ABT‐263, we found we could sensitize T98G and A549 cells to vinblastine when used in combination with a nontoxic concentration of ABT‐263. Taken together, we were able to ascertain vinblastine and ABT‐263 as a potential combination treatment for cancer as identified by the siRNA synthetic lethal screen, indicating siRNA screening technology as an ample method for identifying novel chemosensitivity nodes.