The mutational signature of alkylating damage is highly similar to the one associated with inactivation of NTHL1, a gene involved in Base Excision Repair. We hypothesized that colorectal cancers (CRCs) with high alkylation damage, could be selectively vulnerable to NTHL1 deletion. We found that CRC cells and patient-derived organoids with high alkylation damage, coupled with NTHL1 inactivation, are less viable and exhibit reduced cellular proliferation due to heightened DNA damage repair response and G2/S cell cycle arrest. CHK1 inhibition in this subset of tumors led to enhanced apoptosis. Notably, CRCs with low alkylation, following treatment with alkylating agents, also exhibit vulnerability to NTHL1 deletion and increased sensitivity to CHK1 inhibition. Our study thus demonstrates that the combination of alkylation damage and NTHL1 inactivation leads to synthetic sickness in CRC, further sensitization to CHK1 inhibition, and reveals potential therapeutic vulnerabilities in CRC.
Kim et al. (Tue,) studied this question.