Specific Killing of Rb Mutant Cancer Cells by Inactivating TSC2

SummaryThe retinoblastoma (Rb) tumor suppressor is often inactivated in cancers. To identify genes that can be used to specifically target such cancers, we carried out a genetic screen in Drosophila. We identified gig (fly TSC2) and found that inactivation of rbf (fly Rb) and gig synergistically induced cell death. Interestingly, inactivation of TSC2 specifically kills Rb mutant cancer cells under stress conditions, which is correlated with an inhibition of tumor growth. We show that cancer cell killing induced by concomitant inactivation of Rb and TSC2 is mediated by increased cellular stress, including oxidative stress. Inactivation of TSC2 and Rb synergistically induce oxidative stress via increased protein synthesis, inhibited de novo lipid synthesis, and decreased reactive oxygen species scavenger enzyme SOD2 induction.

► TSC2 Inactivation specifically kills Rb mutant cancer cells
► Inactivation of TSC2 and Rb synergistically induce cellular stress and death
► SC2 inactivation increases ROS through altered protein and lipid metabolisms
► Rb regulates ROS through modulation of SOD2 expression