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Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling
Kristin B Runkle1, Akriti Kharbanda1, Ewa Stypulkowski1
1Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Abstract:
Inappropriate activation of the receptor tyrosine kinase EGFR contributes to a variety of human malignancies. Here we show a mechanism to induce vulnerability to an existing first line treatment for EGFR-driven cancers. We find that inhibiting the palmitoyltransferase DHHC20 creates a dependence on EGFR signaling for cancer cell survival. The loss of palmitoylation increases sustained EGFR signal activation and sensitizes cells to EGFR tyrosine kinase inhibition. Our work shows that the reversible modification of EGFR with palmitate "pins" the unstructured C-terminal tail to the plasma membrane, impeding EGFR activation. We identify by mass spectrometry palmitoylated cysteine residues within the C-terminal tail where mutation of the cysteine residues to alanine is sufficient to activate EGFR signaling promoting cell migration and transformation. Our results reveal that the targeting of a peripheral modulator of EGFR signaling, DHHC20, causes a loss of signal regulation and susceptibility to EGFR inhibitor-induced cell death.
Insights
Inhibiting DHHC20 disrupts EGFR signaling regulation, making cancer cells dependent on this pathway and vulnerable to existing EGFR tyrosine kinase inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Epidermal Growth Factor Receptor (EGFR) is a receptor tyrosine kinase implicated in human cancers.
- Dysregulated EGFR signaling is a key driver in various malignancies, making it a therapeutic target.
Purpose of the Study:
- To elucidate a novel mechanism for sensitizing EGFR-driven cancers to existing therapies.
- To investigate the role of protein palmitoylation in regulating EGFR signaling.
Main Methods:
- Utilized mass spectrometry to identify palmitoylated cysteine residues in EGFR.
- Employed genetic manipulation (mutation of cysteine residues) to assess EGFR signaling.
- Investigated the effect of DHHC20 inhibition on cancer cell survival and EGFR signaling.
Main Results:
- Inhibition of DHHC20 leads to EGFR hyperactivation by disrupting palmitoylation.
- Loss of palmitoylation increases sustained EGFR signaling, creating a dependence on the pathway.
- EGFR-driven cancer cells lacking DHHC20 are sensitized to EGFR tyrosine kinase inhibitors.
Conclusions:
- Palmitoylation of EGFR by DHHC20 acts as a negative regulator of receptor signaling.
- Targeting DHHC20 offers a strategy to re-sensitize tumors to EGFR-targeted therapies.
- This study reveals a druggable target for enhancing cancer treatment efficacy.
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