Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

Abstract

AbstractTo define the growing significance of cellular targets of cancer drugs, we examined the fitness dependency of cellular targets or effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular mediators or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules were approved. Additionally, our analysis recognized 43 cellular targets as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues repurposing approved oncology drugs in cancer types. 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 such 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 in-tended cellular effectors of drug might not be fitness genes and offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.