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

Chia-Hung Chen; Bo-Wei Wang; Yu-Chun Hsiao; Chun-Yi Wu; Fang-Ju Cheng; Te-Chun Hsia; Chih-Yi Chen; Yihua Wang; Zhang Weihua; Ruey-Hwang Chou; Chih-Hsin Tang; Yun-Ju Chen; Ya-Ling Wei; Jennifer L Hsu; Chih-Yen Tu; Mien-Chie Hung; Wei-Chien Huang

doi:10.1038/s41388-021-01889-0

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. Epub 2021 Jun 21.

Authors

Chia-Hung Chen^#^{1

2

3}, Bo-Wei Wang^#^{4

5}, Yu-Chun Hsiao^#^{4

5

6}, Chun-Yi Wu⁷, Fang-Ju Cheng^{6

8

9}, Te-Chun Hsia^{1

3

10}, Chih-Yi Chen¹¹, Yihua Wang^{12

13}, Zhang Weihua¹⁴, Ruey-Hwang Chou^{4

6}, Chih-Hsin Tang^{2

8}, Yun-Ju Chen^{15

16

17}, Ya-Ling Wei⁴, 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.

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.

MeSH terms

Animals
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm* / genetics
ErbB Receptors* / antagonists & inhibitors
ErbB Receptors* / genetics
ErbB Receptors* / metabolism
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Male
Mice
Mice, Nude
Protein Kinase C-delta* / genetics
Protein Kinase C-delta* / metabolism
Protein Kinase Inhibitors* / pharmacology
Protein Kinase Inhibitors* / therapeutic use
Sodium-Glucose Transporter 1* / genetics
Sodium-Glucose Transporter 1* / metabolism
Up-Regulation* / drug effects
Xenograft Model Antitumor Assays

Substances

EGFR protein, human
ErbB Receptors
Protein Kinase C-delta
Protein Kinase Inhibitors
SLC5A1 protein, human
Sodium-Glucose Transporter 1
PRKCD protein, human

Grants and funding

MR/S025480/1/MRC_/Medical Research Council/United Kingdom