Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis
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 resi...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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The Royal Society
2021-10-01
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| Series: | Open Biology |
| Subjects: | |
| Online Access: | https://royalsocietypublishing.org/doi/10.1098/rsob.210033 |
| _version_ | 1797785653467938816 |
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| author | Yasmin A. Kadry Jia-Ying Lee Eric S. Witze |
| author_facet | Yasmin A. Kadry Jia-Ying Lee Eric S. Witze |
| author_sort | Yasmin A. Kadry |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T00:57:01Z |
| format | Article |
| id | doaj.art-584794c5d366488c8f16fcb1d2404cfc |
| institution | Directory Open Access Journal |
| issn | 2046-2441 |
| language | English |
| last_indexed | 2024-03-13T00:57:01Z |
| publishDate | 2021-10-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Open Biology |
| spelling | doaj.art-584794c5d366488c8f16fcb1d2404cfc2023-07-06T16:15:24ZengThe Royal SocietyOpen Biology2046-24412021-10-01111010.1098/rsob.210033Regulation of EGFR signalling by palmitoylation and its role in tumorigenesisYasmin A. Kadry0Jia-Ying Lee1Eric S. Witze2Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAThe 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.https://royalsocietypublishing.org/doi/10.1098/rsob.210033palmitoylationEGFRlungcancersignallingDHHC20 |
| spellingShingle | Yasmin A. Kadry Jia-Ying Lee Eric S. Witze Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis Open Biology palmitoylation EGFR lung cancer signalling DHHC20 |
| title | Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis |
| title_full | Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis |
| title_fullStr | Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis |
| title_full_unstemmed | Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis |
| title_short | Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis |
| title_sort | regulation of egfr signalling by palmitoylation and its role in tumorigenesis |
| topic | palmitoylation EGFR lung cancer signalling DHHC20 |
| url | https://royalsocietypublishing.org/doi/10.1098/rsob.210033 |
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