Abstract A22: Selective inhibition of TOR complex 2 as a means to sensitize cancer cells to DNA damage agents?

The inhibition of the central growth regulatory kinase TOR, which participates in two complexes, TORC1 and TORC2, is the focus of many metabolic and cancer studies. Most studies have dealt with TORC1, the canonical target of rapamycin. However, TORC2 also plays a role in cancer development. In fission yeast, TORC2, through the activation of Gad8 (homologous to AKT in humans), is required for survival under DNA-damaging conditions. TORC2-Gad8 (AKT) is not required for Chk1-dependent DNA damage-induced cell-cycle arrest; however, perturbation of TORC2-Gad8 signaling generates an accumulation of homologous recombination (HR)-Rad52 containing repair foci. In addition, cells lacking TORC2-Gad8 become dependent on the HR pathway for their viability. Thus, we speculate that TORC2-Gad8 signaling affects HR-independent DNA repair pathways. Our most recent results suggest that TORC2-Gad8 is required for specific chromatin modifications that ensure proficient DNA damage repair. Given that the role of TORC2 in DNA damage repair is conserved in human cells, we predict that the selective inhibition of mTORC2 can improve combined therapy, by sensitizing cancer cells to DNA-damaging agents. Chemicogenetic screens that aim at isolating specific TORC2 inhibitors will be described. Citation Format: Adiel Cohen, Emese Pataki, Nuria Vital, Martin Kupiec, Ronit Weisman. Selective inhibition of TOR complex 2 as a means to sensitize cancer cells to DNA damage agents? [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A22.