Here, we prove the feasibility of assigning genes to cancer pathways by genome-wide forward genetics using genome-edited human cell systems, link FOXO3, NCOA3, and TCF7L2 to phenotypes of the EGFR/Ras/MAPK pathway, and implicate FOXO3 and NCOA3 in the response to anti-EGFR therapy. The gene discussed is TCF7L2; the disease is cancer.