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Genetic alterations initiate tumors and enable the evolution of drugresistance. The pro-cancer view of mutations is however incomplete, and severalstudies show that mutational load can reduce tumor fitness. Given its negativeeffect, genetic load should make tumors more sensitive to anticancer drugs.Here, we test this hypothesis across all major types of cancer from the CancerCell Line Encyclopedia, which provides genetic and expression data of 496 celllines together with their response to 24 common anticancer drugs. We found thatthe efficacy of 9 out of 24 drugs showed significant association with geneticload in a pan-cancer analysis. The associations for some tissue-drugcombinations were remarkably strong, with genetic load explaining up to 83% ofthe variance in the drug response. Overall, the role of genetic load dependedon both the drug and the tissue type with 10 tissues being particularlyvulnerable to genetic load. We also identified changes in gene expressionassociated with increased genetic load, which included cell-cycle checkpoints,DNA damage and apoptosis. Our results show that genetic load is an importantcomponent of tumor fitness and can predict drug sensitivity. Beyond being abiomarker, genetic load might be a new, unexplored vulnerability of cancer.

Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia