PKC\u03b4-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs

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

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.

Highlights

The epidermal growth factor receptor (EGFR), a membrane-bound tyrosine kinase receptor, has been found to be a critical oncogene in promoting the tumorigenesis, mitogenesis, and tumor progression of various cancer types, including non-small cell lung cancer (NSCLC) [1, 2]
tyrosine kinase inhibitors (TKIs)-resistant cells are tolerant to autophagic cell death induced by glucose deprivation To determine whether alternation of glucose metabolism plays a role in the development of acquired resistance to EGFR TKIs, we first established erlotinib-resistant (ER) clones from wt EGFRexpressing NSCLC lines NCI-H322 (H322) and NCI-H292 (H292) and from an activating EGFR mutant-expressing HCC827 lung adenocarcinoma cell line by culturing the cells in increasing concentrations of erlotinib
In addition to the inhibition of EGFR downstream PI3K/Akt and MAPK survival pathways, reductions in glucose uptake and glycolysis have been detected in gefitinib-treated lung cancer cells that precede cell cycle suppression and apoptosis induction [22], suggesting that glucose metabolic activity closely reflects the intrinsic response to EGFR TKI-based therapy

Summary

INTRODUCTION

The epidermal growth factor receptor (EGFR), a membrane-bound tyrosine kinase receptor, has been found to be a critical oncogene in promoting the tumorigenesis, mitogenesis, and tumor progression of various cancer types, including non-small cell lung cancer (NSCLC) [1, 2]. Changes in tumor glucose metabolism precede decreases in tumor size in response to EGFR TKIs [22, 24] These findings suggest that reduction of EGFRmediated glycolysis may be involved in the anti-tumor activity of EGFR TKIs, and monitoring [18F]-FDG-PET uptake has been used to predict therapeutic responses to EGFR TKIs in lung cancer patients [25,26,27]. Suppression of facilitative glucose transporter Glut was found to mediate the anti-cancer activity of TKIs in NSCLC cell lines bearing wild-type (wt) or mutant EGFR [28]. These studies suggested that the suppression of glucose uptake and metabolism may be essential to achieve the therapeutic response of EGFR TKIs in NSCLC patients. Our results elucidate the metabolic mechanism underlying the development of acquired resistance to EGFR TKIs and indicate that targeting PKCδ/SGLT1 in combination with EGFR TKIs may benefit NSCLC patients

RESULTS

DISCUSSION

CONFLICT OF INTEREST