Oxidative base damage to telomeres sensitizes cancer cells to ATR inhibition.

Targeted inhibition of DNA damage response proteins has received significant clinical attention owing to the success of PARP inhibitors. Due to G1/S checkpoint inactivation, cancer cells are reliant on the G2/M checkpoint to cope with elevated DNA replication stress. We demonstrated that a single induction of 8-oxo-guanine at telomeres in cancer cells was sufficient to induce replication stress but was not cytotoxic. Here, we find inhibition of ATR, CHK1, or WEE1 after induction of telomeric 8-oxo-guanine significantly reduced cell viability by inducing genome instability. This occurred at doses markedly less than those required to increase instability in non-cancerous cells. We determined the mechanism of this instability is due to insufficient levels of RPA for damaged telomeres, forcing cells to progress through S-phase with telomere damage and exit G2-phase prematurely, prolonging mitosis. This study demonstrates targeted oxidative base damage at telomeres can enhance the therapeutic efficacy of ATR inhibition in cancer.