Mutational signatures are markers of drug sensitivity of cancer cells.

Genomic analyses have revealed mutational footprints associated with DNA maintenance gone awry, or with mutagen exposures. Because cancer therapeutics often target DNA synthesis or repair, we asked if mutational signatures make useful markers of drug sensitivity. We detect mutational signatures in cancer cell line exomes (where matched healthy tissues are not available) by adjusting for the confounding germline mutation spectra across ancestries. We identify robust associations between various mutational signatures and drug activity across cancer cell lines; these are as numerous as associations with established genetic markers such as driver gene alterations. Signatures of prior exposures to DNA damaging agents - including chemotherapy - tend to associate with drug resistance, while signatures of deficiencies in DNA repair tend to predict sensitivity towards particular therapeutics. Replication analyses across independent drug and CRISPR genetic screening data sets reveal hundreds of robust associations, which are provided as a resource for drug repurposing guided by mutational signature markers.