Palmitoylation makes the switch for EGFR

Abstract

Cancer Aberrant epidermal growth factor receptor (EGFR) signaling through two important pathways, RAS–mitogen-activated protein kinase (RAS-MAPK) and phosphatidylinositol 3-kinase (PI3K), promotes tumor growth. EGFR inhibitors are rarely effective in tumors with mutations in the protein KRAS, which stimulate the MAPK pathway independently of EGFR activity. Kharbanda et al. found that EGFR palmitoylated on the intracellular tail interacted preferentially with a PI3K subunit rather than a MAPK adaptor protein. Blocking palmitoylation reduced PI3K signaling activity and sensitized cells to PI3K inhibitors. These results explain why EGFR inhibitors are effective only in cancer cells in which EGFR is palmitoylated. Sci. Signal. 13 , eaax2364 (2020).