Blocking EGFR palmitoylation suppresses PI3K signaling and mutant KRAS lung tumorigenesis.

Science Signaling
Akriti KharbandaEric S Witze

Abstract

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 palmitoylatio...Continue Reading

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Citations

Jan 14, 2021·International Journal of Molecular Sciences·Alexandru OpritaAni-Simona Sevastre
Nov 22, 2020·The Journal of Biological Chemistry·Martin Ian P MalgapoMaurine E Linder
Jan 13, 2021·The Journal of Biological Chemistry·Martin Ian P MalgapoMaurine E Linder
Apr 1, 2021·Open Biology·Luke H ChamberlainGwyn W Gould
Jun 17, 2021·Molecular Biology Reports·M Janaki Ramaiah, K Rohil Kumar
Jul 10, 2021·Progress in Lipid Research·Do-Hyeon KimSung Ho Ryu
Jul 27, 2021·ACS Chemical Biology·Saara-Anne AziziBryan C Dickinson
Aug 4, 2021·Open Biology·Consuelo Coronel ArrecheaJavier Valdez Taubas
Sep 2, 2021·Current Opinion in Chemical Biology·Tong LanBryan C Dickinson
Sep 5, 2020·Recent Patents on Anti-cancer Drug Discovery·Long WangZuoyi Jiao
Oct 2, 2021·Frontiers in Cell and Developmental Biology·Maxim L BychkovEkaterina N Lyukmanova
Oct 6, 2021·Open Biology·Yasmin A KadryEric S Witze
Nov 6, 2021·Biology of the Cell·Maxime Jansen, Bruno Beaumelle

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