Many tumours bear a high number of mutations due to an antiviral defence mechanism, the APOBEC family of enyzmes. This can accidentally activate during carcinogenesis, due to largely unknown causes, damaging DNA and causing abundant mutations. Healthy somatic cells of various tissues, remarkably, rarely exhibit APOBEC mutagenesis, suggesting that APOBECs could provide a novel way to selectively target malignant cells while sparing healthy ones.
We have found that the HMCES enzyme – a recently discovered DNA damage sensor – to be the Achilles heel of some lung tumours, specifically those with a highly active APOBEC3A system. Our study found that blocking HMCES is very damaging to cells with an expressed APOBEC3A enyzme (which are many lung cancer cells), but much less so for the genetically identical cell line but in which APOBEC is switched off. In addition to the lung adenocarcinoma, APOBEC3A enzyme mutagenizes other cancer types, most notably breast, head-and-neck and bladder cancers and sarcomas, suggesting a broad application of this finding.
Genetic screening experiments were performed using CRISPR/Cas9 on several types of human lung cancer cell lines, which we engineered to mimic tumors in their ability to overexpress APOBEC3A and cause DNA damage and mutations. The HMCES gene was a recurrent ‘hit’ in this genome-wide search. Moreover a genomic analysis across ~100 cell lines indicated that APOBEC-mutated cells of diverse genetic backgrounds poorly tolerate editing of the HMCES gene. This supported that HMCES can provide a therapeutic avenue, effective in different individuals. Additionally, in a genetic screen in cells where the TP53 gene was ablated (a common occurence in tumors, but a rare one in noncancerous somatic cells), the effects of HMCES inhibition were boosted.
Overall, inhibiting HMCES may selectively destroy the hypermutating, rapidly evolving cells within a lung tumor mass, hampering the cancer’s ability to adapt to drug treatments and to gain new driver mutations. We suggest that new approaches to cancer therapy might focus on targeting hypermutating cells to slow down tumor evolution.