Blocking EGFR palmitoylation suppresses PI3K signaling and mutant KRAS lung tumorigenesis
- 2 March 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 13 (621)
- https://doi.org/10.1126/scisignal.aax2364
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 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.Funding Information
- National Institutes of Health (R01CA181633)
- American Cancer Society (RSG-15-027-01)
This publication has 23 references indexed in Scilit:
- Comprehensive molecular profiling of lung adenocarcinomaNature, 2014
- Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor MaintenanceCancer Cell, 2013
- Targeting the EGFR signaling pathway in cancer therapyEmerging Therapeutic Targets, 2012
- Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinaseNature Protocols, 2009
- Defining Molecular Cornerstones during Fibroblast to iPS Cell Reprogramming in MouseCell Stem Cell, 2008
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- PIK3CA mutation and amplification in human lung cancerPathology International, 2007
- Phosphatidylinositol-3-OH Kinase or RAS Pathway Mutations in Human Breast Cancer Cell LinesMolecular Cancer Research, 2007
- The Differential Effects of Mutant p53 Alleles on Advanced Murine Lung CancerCancer Research, 2005
- Phosphorylation by Glycogen Synthase Kinase-3 Controls c-Myc Proteolysis and Subnuclear LocalizationJournal of Biological Chemistry, 2003