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Updated: Oct 18, 2025
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis
Yasmin A Kadry1, Jia-Ying Lee1, Eric S Witze1
1Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic target is overshadowed by the inevitable drug resistance that develops. Overcoming resistance mechanisms requires a deeper understanding of EGFR regulation in cancer cells. In this review, we discuss our recent discovery that the palmitoyltransferase DHHC20 palmitoylates EGFR on the C-terminal domain and plays a critical role in signal regulation during oncogenesis. Inhibiting DHHC20 expression or mutating the palmitoylation site on EGFR alters the EGF-induced signalling kinetics from a transient signal to a sustained signal. The change in signalling is accompanied by a decrease in cell proliferation in multiple human cancer cell lines. Our in vivo studies demonstrate that ablating the gene Zdhhc20 by CRISPR/Cas9-mediated inhibition in a mouse model of oncogenic Kras-driven lung adenocarcinoma potently inhibits tumorigenesis. The negative effect on tumorigenesis is mediated by EGFR since the expression of a palmitoylation-resistant mutant form of EGFR also inhibits Kras-driven lung adenocarcinoma. Finally, reducing EGFR palmitoylation increases the sensitivity of multiple cancer cell lines to existing inhibitors of EGFR and downstream signalling effector pathways. We will discuss the implications of these effects and strategies for targeting these new vulnerabilities.
Insights
DHHC20 palmitoylation of epidermal growth factor receptor (EGFR) regulates oncogenic signaling. Inhibiting this process or EGFR palmitoylation reduces cancer cell proliferation and tumor growth, enhancing sensitivity to existing therapies.
Area of Science:
- Molecular oncology
- Signal transduction
- Cancer therapeutics
Background:
- Epidermal growth factor receptor (EGFR) is a key driver in many cancers, with inhibitors representing early targeted therapies.
- Drug resistance to EGFR inhibitors is a significant clinical challenge, necessitating a deeper understanding of EGFR regulation.
Purpose of the Study:
- To investigate the role of DHHC20 palmitoyltransferase in EGFR signaling and oncogenesis.
- To explore the therapeutic potential of targeting EGFR palmitoylation.
Main Methods:
- Investigated DHHC20-mediated palmitoylation of EGFR in cancer cell lines.
- Utilized CRISPR/Cas9 to ablate the mouse gene Zdhhc20 in a lung adenocarcinoma model.
- Assessed the impact of EGFR palmitoylation site mutations on signaling and tumor growth.
- Evaluated the effect of reduced EGFR palmitoylation on cancer cell sensitivity to EGFR inhibitors.
Main Results:
- DHHC20 palmitoylates EGFR, critically regulating its signal transduction during oncogenesis.
- Inhibition of DHHC20 or EGFR palmitoylation shifts EGF-induced signaling from transient to sustained, decreasing cell proliferation.
- Ablation of Zdhhc20 in a mouse model potently inhibited Kras-driven lung adenocarcinoma, mediated by EGFR.
- Reduced EGFR palmitoylation enhanced cancer cell sensitivity to EGFR inhibitors and downstream pathway inhibitors.
Conclusions:
- DHHC20-mediated EGFR palmitoylation is a novel regulatory mechanism in oncogenesis.
- Targeting DHHC20 or EGFR palmitoylation represents a promising strategy to overcome resistance and enhance existing cancer therapies.
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