Genome-wide profiling identifies the genetic dependencies of cell death following EGFR inhibition

Abstract

EGFR is a proto-oncogene that is mutationally activated in a variety of cancers. Small molecule inhibitors targeting EGFR can be effective in slowing the progression of disease, and in some settings these drugs even cause dramatic tumor regression. However, responses to EGFR inhibitors are rarely durable, and the mechanisms contributing to response variation remain unclear. In particular, several distinct mechanisms have been proposed for how EGFR inhibition activates cell death, and a consensus has yet to emerge. In this study, we use functional genomics with specialized analyses to infer how genetic perturbations effect the drug-induced death rate. Our data clarify that inhibition of PI3K signaling drives the lethality of EGFR inhibition. Inhibition of other pathways downstream of EGFR, including the RAS-MAPK pathway, promote growth suppression, but not the lethal effects of EGFR inhibitors. Taken together, our study reveals the first "reference map" for the genome-wide genetic dependencies of lethality for EGFR inhibitors.