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.
Highlights
A delicate balance between multiple convergent signalling pathways can tip the scale between homeostatic and oncogenic signalling
We found that the C1025A epidermal growth factor receptor (EGFR)-mutant had increased association with Grb2, a scaffold protein that binds to the phosphorylated C-terminal domain (CTD) of activated EGFR, compared to wild-type EGFR [21]
It is possible that palmitoylation follows EGFR activation and tyrosine phosphorylation of the CTD, it is currently unclear if DHHC20 exhibits a preference for phosphorylated or unphosphorylated CTD
Summary
A delicate balance between multiple convergent signalling pathways can tip the scale between homeostatic and oncogenic signalling. Growth factor receptor signalling is a frequently dysregulated pathway in multiple cancer types. The epidermal growth factor receptor (EGFR) is one of the most frequently mutated oncogenes in lung cancer and other cancer types [1]. EGFR is a receptor tyrosine kinase that transduces signalling cascades across the plasma membrane, from the extracellular to intracellular environment [2]. Mutations and deletions in EGFR promote oncogenic signalling by enhancing the kinase activity of EGFR [3]. We have recently determined EGFR is palmitoylated, and through biochemical and in vivo studies have demonstrated. This modification inhibits receptor signalling activity and plays a critical role in cancer initiation and growth in specific cellular contexts
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