In summary, we demonstrate that lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1, and propose that specifically targeting both kinase and Rheb-GEF activities of EGFR (e.g., BIEGi-1) is a promising therapeutic strategy for cancer patients with EGFR mutations, as illustrated in Fig. 6h. The gene discussed is EGFR; the disease is cancer.