Systematic Analysis of Drug Vulnerabilities Conferred by Tumor Suppressor Loss

Abstract

In addition to oncogene inhibition, targeting tumor suppressor deficiency could provide potential venues for precision cancer medicine. However, the full spectrum of drug vulnerability conferred by tumor suppressor loss remains unclear. We systematically analyzed how loss of 59 common tumor suppressors each affected cellular sensitivity to 26 different types of anticancer therapeutics. The experiments were performed in a one-gene, one-drug manner, and through such a large gene-drug iteration study, we were able to generate a drug sensitivity map that describes numerous examples of drug resistance or hypersensitivity conferred by tumor suppressor loss. We further delineated the mechanisms of several gene-drug interactions, showing that loss of tumor suppressors could modify drug sensitivity at various steps of drug action. This systematic drug sensitivity map highlights potential drug vulnerabilities associated with tumor suppressor loss, which may help expand precision cancer medicine on the basis of tumor suppressor status.

Keywords: BAP1; CREBBP; SETD2; drug sensitivity; tumor suppressor.