An autophagy-inducing stapled peptide promotes c-MET degradation and overrides adaptive resistance to sorafenib in c-MET+ hepatocellular carcinoma

Shan Gao, Na Li, Xiaozhe Zhang, Jingyi Chen, Ben C.B. Ko, Yanxiang Zhao

Research output: Journal article publicationJournal articleAcademic researchpeer-review

4 Citations (Scopus)

Abstract

Background: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer cases and ranks as the second leading cause of cancer related death. Multiple receptor tyrosine kinases such as EGFR, FGFR and c-MET have been shown to drive tumorigenesis and progression of HCC. However, tyrosine kinase inhibitors (TKIs) that target these kinases, including the FDA-approved sorafenib, only offer limited clinical success. Resistance to sorafenib and other TKIs also readily emerge in HCC patients, further limiting the usage of these drugs. Novel therapeutic strategies are needed to address the urgent unmet medical need for HCC patients. Results: Autophagy is an evolutionally conserved lysosome-dependent degradation process that is also functionally implicated in HCC. We previously developed an autophagy-inducing stapled peptide (Tat-SP4) that induced autophagy and endolysosomal degradation of EGFR in lung cancer and breast cancer cells. Here we present data to show that Tat-SP4 also induced significant autophagic response in multiple HCC cell lines and promoted the endolysosomal degradation of c-MET to attenuate its downstream signaling activities although it didn't affect the intrinsically fast turnover of EGFR. Tat-SP4 also overrode adaptive resistance to sorafenib in c-MET+ HCC cells but employed the distinct mechanism of inducing non-apoptotic cell death. Conclusion: With its distinct mechanism of promoting autophagy and endolysosomal degradation of c-MET, Tat-SP4 may serve as a novel therapeutic agent that complement and synergize with sorafenib to enhance its clinical efficacy in HCC patients.

Original languageEnglish
Article number101412
JournalBiochemistry and Biophysics Reports
Volume33
DOIs
Publication statusPublished - Mar 2023

Keywords

  • Autophagy
  • c-MET
  • EGFR
  • Endolysosomal degradation
  • HCC

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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