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.


Non–small cell lung cancer (NSCLC) is often characterized by mutually exclusive mutations in the epidermal growth factor receptor (EGFR) or the guanosine triphosphatase KRAS. We hypothesized that blocking EGFR palmitoylation, previously shown to inhibit EGFR activity, might alter downstream signaling in the KRAS-mutant setting. Here, we found that blocking EGFR palmitoylation, by either knocking down the palmitoyltransferase DHHC20 or expressing a palmitoylation-resistant EGFR mutant, reduced activation of the kinase PI3K, the abundance of the transcription factor MYC, and the proliferation of cells in culture, as well as reduced tumor growth in a mouse model of KRAS-mutant lung adenocarcinoma. Knocking down DHHC20 reduced the growth of existing tumors derived from human KRAS-mutant lung cancer cells and increased the sensitivity of these cells to a PI3K inhibitor. Palmitoylated EGFR interacted with the PI3K regulatory subunit PIK3R1 (p85) and increased the recruitment of the PI3K heterodimer to the plasma membrane. Alternatively, blocking palmitoylation increased the association of EGFR with the MAPK adaptor Grb2 and decreased that with p85. This binary switching between MAPK and PI3K signaling, modulated by EGFR palmitoylation, was only observed in the presence of oncogenic KRAS. These findings suggest a mechanism whereby oncogenic KRAS saturates signaling through unpalmitoylated EGFR, reducing formation of the PI3K signaling complex. Future development of DHHC20 inhibitors to reduce EGFR-PI3K signaling could be beneficial to patients with KRAS-mutant tumors.

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