Research ArticleCancer

Blocking EGFR palmitoylation suppresses PI3K signaling and mutant KRAS lung tumorigenesis

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Science Signaling  03 Mar 2020:
Vol. 13, Issue 621, eaax2364
DOI: 10.1126/scisignal.aax2364

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An EGFR pathway switch

Epidermal growth factor receptor (EGFR) signaling through generally two pathways, RAS-MAPK and PI3K-AKT, stimulates cell proliferation and survival; as such, EGFR is an attractive therapeutic target to inhibit tumor growth. However, EGFR inhibitors are rarely effective in tumors with KRAS mutations, which are common and result in MAPK pathway stimulation independently of EGFR activity. One exception is when the intracellular tail region of EGFR is palmitoylated. Kharbanda et al. found that this may be because the palmitoylated EGFR interacts preferentially with a PI3K subunit rather than a MAPK adaptor protein. Blocking palmitoylation reduced PI3K signaling activity, sensitizing cells to PI3K inhibitors. These findings may help clinicians determine which KRAS-mutant patients could benefit from EGFR inhibitors and, with future palmitoyltransferase inhibitors, better restrict these two pathways that commonly and reciprocally drive drug resistance.

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