PKCδ-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs

  • Oncogene. 2021 Jul;40(29):4796-4808. doi: 10.1038/s41388-021-01889-0.
Chia-Hung Chen  #  1  2  3 ,  Bo-Wei Wang  #  4  5 ,  Yu-Chun Hsiao  #  4  5  6 ,  Chun-Yi Wu  7 ,  Fang-Ju Cheng  6  8  9 ,  Te-Chun Hsia  1  3  10 ,  Chih-Yi Chen  11 ,  Yihua Wang  12  13 ,  Zhang Weihua  14 ,  Ruey-Hwang Chou  4  6 ,  Chih-Hsin Tang  2  8 ,  Yun-Ju Chen  15  16  17 ,  Ya-Ling Wei  4 ,  Jennifer L Hsu  4  9 ,  Chih-Yen Tu  18  19 ,  Mien-Chie Hung  20  21  22 ,  Wei-Chien Huang  23  24  25  26
Affiliations
  • 1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
  • 2. School of Medicine, China Medical University, Taichung, Taiwan.
  • 3. Department of Respiratory Therapy, China Medical University, Taichung, Taiwan.
  • 4. Center for Molecular Medicine, Research Center for Cancer Biology, and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 5. Drug Development Center, China Medical University, Taichung, Taiwan.
  • 6. The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
  • 7. Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
  • 8. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
  • 9. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 10. Department of Internal Medicine, Hyperbaric Oxygen Therapy Center, China Medical University Hospital, Taichung, Taiwan.
  • 11. Division of Thoracic Surgery, Department of Surgery, Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
  • 12. Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK.
  • 13. Institute for Life Sciences, University of Southampton, Southampton, UK.
  • 14. Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
  • 15. Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.
  • 16. School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.
  • 17. Department of Pharmacy, E-Da Hospital, Kaohsiung, Taiwan.
  • 18. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan. [email protected].
  • 19. School of Medicine, China Medical University, Taichung, Taiwan. [email protected].
  • 20. Center for Molecular Medicine, Research Center for Cancer Biology, and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. [email protected].
  • 21. Drug Development Center, China Medical University, Taichung, Taiwan. [email protected].
  • 22. The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan. [email protected].
  • 23. Center for Molecular Medicine, Research Center for Cancer Biology, and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. [email protected].
  • 24. Drug Development Center, China Medical University, Taichung, Taiwan. [email protected].
  • 25. The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan. [email protected].
  • 26. Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan. [email protected].
  • # Contributed equally.
PMID: 34155348 DOI: 10.1038/s41388-021-01889-0
Abstract

The tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for non-small cell lung Cancer (NSCLC) patients, but the development of acquired resistance remains a therapeutic hurdle. The reduction of glucose uptake has been implicated in the anti-tumor activity of EGFR TKIs. In this study, the upregulation of the active sodium/glucose co-transporter 1 (SGLT1) was found to confer the development of acquired EGFR TKI resistance and was correlated with the poorer clinical outcome of the NSCLC patients who received EGFR TKI treatment. Blockade of SGLT1 overcame this resistance in vitro and in vivo by reducing glucose uptake in NSCLC cells. Mechanistically, SGLT1 protein was stabilized through the interaction with PKCδ-phosphorylated (Thr678) EGFR in the TKI-resistant cells. Our findings revealed that PKCδ/EGFR axis-dependent SGLT1 upregulation was a critical mechanism underlying the acquired resistance to EGFR TKIs. We suggest co-targeting PKCδ/SGLT1 as a potential strategy to improve the therapeutic efficacy of EGFR TKIs in NSCLC patients.

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