We showed that the ATR mutation increases cell sensitivity to several molecules. Amongst them, SN-38 (active metabolite of Irinotecan, topoisomerase I inhibitor) and VE-822 (ATR inhibitor) were those that showed the most dramatic sensitization of ATR mutant cells. The combination of both molecules resulted in highly synergistic effects, reaching a maximum of 50%...Altogether, these results highlight the cytotoxic sensitization of ATR mutant cells to topoisomerase I and ATR inhibitors, either used separately or combined. The combined (SN-38 + VE-822) treatment greatly enhanced apoptosis induction, especially in ATR mutant cells.