2. Academic Validation
  3. Diarylheptanoid 35d overcomes EGFR TKI resistance by inducing hsp70-mediated lysosomal degradation of EGFR in EGFR-mutant lung adenocarcinoma

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

  • J Biol Chem. 2023 May 11;104814. doi: 10.1016/j.jbc.2023.104814.
Xuan Hong 1,  Min-Tsang Hsieh 2,  Tzu-Yu Tseng 3,  Hui-Yi Lin 4,  Hung-Chih Chang 3,  Sir-Theng Yau 3,  Wei-Chung Cheng 5,  Baozhen Ke 6,  Hsiao-Hui Liao 3,  Chih-Ying Wu 7,  An-An Liu 3,  Meei-Maan Wu 8,  Kuo-Yen Huang 9,  Pan-Chyr Yang 10,  Sheng-Chu Kuo 11,  Mien-Chie Hung 12,  Pei-Chih Lee 13
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
  • 2 School of Pharmacy, China Medical University, Taichung, Taiwan; Research Center for Chinese Herbal Medicine, China Medical University, Taichung, Taiwan; Chinese Medicinal Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
  • 3 Research Center for Cancer Biology, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 4 Research Center for Chinese Herbal Medicine, China Medical University, Taichung, Taiwan.
  • 5 Research Center for Cancer Biology, China Medical University, Taichung, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, China Medical University, Taichung, Taiwan.
  • 6 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 7 Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
  • 8 Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; School of Public Health, College of Public Health, Taipei Medical University, Taipei 11031, Taiwan; Master Program in Applied Epidemiology, College of Public Health, Taipei Medical University, Taipei 11031, Taiwan.
  • 9 Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
  • 10 Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan; Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
  • 11 School of Pharmacy, China Medical University, Taichung, Taiwan; Research Center for Chinese Herbal Medicine, China Medical University, Taichung, Taiwan.
  • 12 Research Center for Cancer Biology, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. Electronic address: mhung@cmu.edu.tw.
  • 13 Research Center for Cancer Biology, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. Electronic address: antiolde333@gmail.com.
PMID: 37178919 DOI: 10.1016/j.jbc.2023.104814
Abstract

EGFR-mutant lung adenocarcinomas (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 hsp70-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 re-progression 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.

Keywords

EGFR; EGFR mutation; TKI resistance; TKI-insensitive EGFR signaling; lung adenocarcinoma; lung cancer.

Figures
Products