Ganoderma microsporum immunomodulatory protein as an extracellular epidermal growth factor receptor (EGFR) degrader for suppressing EGFR-positive lung cancer cells

Wei Jyun Hua, Hsin Yeh, Zhi Hu Lin, Ai Jung Tseng, Li Chen Huang, Wei Lun Qiu, Tsung Hsi Tu, Ding Han Wang, Wei Hung Hsu, Wei Lun Hwang, Tung Yi Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Epidermal growth factor receptor (EGFR) abnormalities relevant to tumor progression. A newly developed strategy for cancer therapy is induction of EGFR degradation. GMI, an immunomodulatory protein from the medicinal mushroom Ganoderma microsporum, exhibits anticancer activity. However, its role in the intracellular trafficking and degradation of EGFR remains unclear. In this study, we discovered that GMI inhibits the phosphorylation of multiple tyrosine kinases. Specifically, GMI was discovered to suppress lung cancer cells harboring both wild-type and mutant EGFR by inhibiting EGFR dimerization and eliminating EGFR-mediated signaling. Functional studies revealed that GMI binds to the extracellular segment of EGFR. GMI interacts with EGFR to induce phosphorylation of EGFR at tyrosine1045, which triggers clathrin-dependent endocytosis and degradation of EGFR. Furthermore, in the mouse models, GMI was discovered to suppress tumor growth. Knockdown of EGFR in lung cancer cells abolishes GMI's anticancer activity in vivo and in vitro. Our results reveal the interaction mechanisms through which GMI induces EGFR degradation and abolishes EGFR-mediated intracellular pathway. Our study indicates that GMI is an EGFR degrader for inhibiting EGFR-expressing tumor growth.

Original languageEnglish
Article number216458
JournalCancer Letters
Volume578
DOIs
StatePublished - 1 Dec 2023

Keywords

  • Degrader
  • Epidermal growth factor receptor
  • Ganoderma microsporum immunomodulatory protein
  • Non-small cell lung cancer

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