Diarylheptanoid 35d overcomes EGFR TKI resistance by inducing hsp70-mediated lysosomal degradation of EGFR in EGFR-mutant lung adenocarcinoma

Xuan Hong, Min Tsang Hsieh, Tzu Yu Tseng, Hui Yi Lin, Hung Chih Chang, Sir Theng Yau, Wei Chung Cheng, Baozhen Ke, Hsiao Hui Liao, Chih Ying Wu, An An Liu, Meei Maan Wu, Kuo Yen Huang, Pan Chyr Yang, Sheng Chu Kuo, Mien Chie Hung, Pei Chih Lee

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients often respond to EGFR tyrosine kinase inhibitors (TKIs) initially but eventually develop resistance to TKIs. The switch of EGFR downstream signaling from TKI-sensitive to TKI-insensitive is a critical mechanism-driving resistance to TKIs. Identification of potential therapies to target EGFR effectively is a potential strategy to treat TKI-resistant LUADs. In this study, we developed a small molecule diarylheptanoid 35d, a curcumin derivative, that effectively suppressed EGFR protein expression, killed multiple TKI-resistant LUAD cells in vitro, and suppressed tumor growth of EGFR-mutant LUAD xenografts with variant TKI-resistant mechanisms including EGFR C797S mutations in vivo. Mechanically, 35d triggers heat shock protein 70–mediated lysosomal pathway through transcriptional activation of several components in the pathway, such as HSPA1B, to induce EGFR protein degradation. Interestingly, higher HSPA1B expression in LUAD tumors associated with longer survival of EGFR-mutant, TKI-treated patients, suggesting the role of HSPA1B on retarding TKI resistance and providing a rationale for combining 35d with EGFR TKIs. Our data showed that combination of 35d significantly inhibits tumor reprogression on osimertinib and prolongs mice survival. Overall, our results suggest 35d as a promising lead compound to suppress EGFR expression and provide important insights into the development of combination therapies for TKI-resistant LUADs, which could have translational potential for the treatment of this deadly disease.

Original languageEnglish
Article number104814
JournalJournal of Biological Chemistry
Volume299
Issue number6
DOIs
Publication statusPublished - Jun 2023

Keywords

  • EGFR
  • EGFR mutation
  • lung adenocarcinoma
  • lung cancer
  • TKI resistance
  • TKI-insensitive EGFR signaling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Diarylheptanoid 35d overcomes EGFR TKI resistance by inducing hsp70-mediated lysosomal degradation of EGFR in EGFR-mutant lung adenocarcinoma'. Together they form a unique fingerprint.

Cite this