Dual Roles of Lactate in EGFR-TKI-Resistant Lung Cancer by Targeting GPR81 and MCT1

Ruishuang Ma; Xin Li; Shengping Gong; Xiaoqin Ge; Ting Zhu; Xiaoxu Ge; Lijuan Weng; Qingsong Tao; Jianxin Guo

doi:10.1155/2022/3425841

Dual Roles of Lactate in EGFR-TKI-Resistant Lung Cancer by Targeting GPR81 and MCT1

J Oncol. 2022 Dec 12:2022:3425841. doi: 10.1155/2022/3425841. eCollection 2022.

Authors

Ruishuang Ma^{1

2}, Xin Li³, Shengping Gong¹, Xiaoqin Ge¹, Ting Zhu¹, Xiaoxu Ge¹, Lijuan Weng¹, Qingsong Tao¹, Jianxin Guo¹

Affiliations

¹ Department of Radiotherapy and Chemotherapy, Ningbo First Hospital, Ningbo, China.
² Central Laboratory of the Medical Research Center, Ningbo First Hospital, Ningbo, China.
³ Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.

Abstract

Lactate is critical in modeling tumor microenvironment causing chemotherapy resistance; however, the role of lactate in tyrosine kinase inhibitor (TKI) resistance has not been fully known. The aim of this study was to evaluate whether lactate could mediate TKI resistance through GPR81 and MCT1 in non-small-cell lung cancer (NSCLC). Here, we showed that lactate enhanced the cell viability and restrained erlotinib-induced apoptosis in PC9 and HCC827 cells. GPR81 and AKT expression were significantly increased with the addition of lactate, and siGPR81 reduced AKT expression resulting in a raised apoptosis rate with erlotinib treatment. Furthermore, we found that lactate also promoted MCT1 exposure, and inhibiting MCT1 with AZD3965 markedly impaired the glycolytic capacity. A significant increase of GPR81 and MCT1 expression was observed in insensitive tissues compared with sensitive ones by immunostaining in NSCLC patients. Our results indicate that lactate adopts dual strategies to promote TKI resistance in NSCLC, not only activating AKT signaling by GPR81, but also giving energy supply through MCT1-mediated input. Targeting GPR81 and MCT1 may provide new therapeutic modalities for TKI resistance in NSCLC.