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Cellular Fitness Phenotypes of Cancer Target Genes in Cancer Therapeutics

To define the growing significance of cellular targets of targeted cancer drugs, we examined the fitness dependency of cancer drug targets across human cancer cells in a CRISPR-Cas9 fitness screening dataset wherein cellular genes were selectively knocked out before assaying for their fitness dependency in cancer cell lines representing 19 cancer types. We observed that the deletion of 35 out of 47 fitness targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting these molecules were approved. This raised the possibility of undesirable off-target effects of these drugs in such cancers. Additionally, our analysis recognized 43 drug targets which were fitness genes observed in several cancer types as candidate targets for repurposing approved oncology drugs in cancer types in which these drugs were not approved. For example, we found the widespread upregulation and fitness dependency of the components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these targets and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which these drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended drug targets are not fitness genes. The study also offers a rationale for repurposing approved oncology drugs for cancer types that have significant fitness dependency on cellular targets of such approved drugs.