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

Abstract

To define the global significance of cellular targets oncology drug in cancer, we examined the fitness-dependency - the loss of cancer cell’s viability in the absence of a test gene, of cancer drug targets across human cancer cells in a CRISPR-Cas9 fitness screening dataset, wherein genes were selectively knocked-down before assaying for the fitness-dependency of 7470 genes in 324 cancer cell lines representing 19 cancer-types. We observed that depletion of 35 out of 47 fitness targets of oncology drugs did not result in an otherwise expected loss of cell fitness in appropriate cancer-types for which drugs targeting these molecules were approved. This raises the possibility of undesirable drug-associated off-target effects in such cancers. In addition, our analysis allowed recognition of 41 drug targets as fitness genes in several cancer-types as candidate targets for repurposing approved oncology drugs for cancer-types in which these drugs were not approved. For example, we found widespread upregulation and associated reduction in the duration of overall survival of cancer patients, and fitness-dependency of the components of mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins and pemetrexed in certain cancers) in breast and other hard-to-treat cancers for which these drugs are not approved. In brief, the present analysis raises caution about the likelihood of off-target and undesirable drug-associated effects of certain oncology drugs in a subset of cancers where intended drug targets are not fitness genes. This also offers a rationale for repurposing a set of approved oncology drugs for cancer-types that have significant fitness-dependency on a set of cellular targets of such approved drugs.PreciseThis study provides the global significance of cellular targets oncology drugs in maintaining the cellular fitness of cancer-types for which drugs targeting these cellular targets have been approved or not approved across 19 cancer-types.