Mutational signatures are markers of drug sensitivity of cancer cells

Genomic analyses have revealed mutational signatures that are associated with DNA maintenance gone awry, a common occurrence in tumors. Because cancer therapeutics often target synthesis of DNA building blocks, DNA replication or DNA repair, we hypothesized that mutational signatures would make useful markers of drug sensitivity. We rigorously tested this hypothesis by a global analysis of various drug screening and genetic screening data sets, derived from cancer cell line panels. We introduce a novel computational method that detects mutational signatures in cell lines by stringently adjusting for the confounding germline mutational processes, which are difficult to remove when healthy samples from the same individuals are not available. This revealed many associations between diverse mutational signatures and drug activity in cancer cell lines, which are comparably or more numerous than associations with classical genetic features such as cancer driver mutations or copy number alterations. Validation across independent drug screening data and across genetic screens involving drug target genes revealed hundreds of robustly supported associations, which are provided as a resource for drug repurposing guided by mutational signature markers. We suggest that cancer cells bearing genomic signatures of deficiencies in certain DNA repair pathways may be vulnerable to particular types of therapeutics, such as epigenetic drugs.