Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

Hengyi Chen,Yubo Wang,Caiyu Lin,Mingxia Feng,Cheng Hu,Fenfen Sun,Li Li,Yong He,Tao Peng,Conghua Lu,Rui Han

doi:10.1038/s41419-020-2307-5

Abstract

Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an important cause of alectinib resistance. Furthermore, Gab1 was a key effector in the HGF/MET signal transduction pathway that mediated alectinib resistance. The antidiabetic drug metformin combined with alectinib overcame alectinib resistance triggered by HGF/MET through disrupting the complex between MET and Gab1, thereby inhibiting Gab1 phosphorylation and the activation of downstream signal transduction pathways. These results suggest that metformin combined with alectinib may be useful for overcoming alectinib resistance induced by the activation of the HGF/MET signalling pathway and improving the efficacy of alectinib.

Highlights

The first-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) crizotinib has multiple kinase inhibitory activities against ALK, MET, and ROS1, and it shows promising efficacy for non-smallcell lung cancer (NSCLC) patients carrying the ALK gene rearrangement[1,2]
Previous studies have found evidence that MET receptor expression is significantly increased in ALK-positive NSCLC10 and that the tumour microenvironment is altered during TKI treatment, which may increase the production of Hepatocyte growth factor (HGF) and contribute to resistance onset[18]
Alectinib treatment did not inhibit MET phosphorylation but instead increased MET phosphorylation at the measured time points (12, 24, or 48 h) (Fig. 1b). These results suggest that HGF/MET signalling is activated after treatment with alectinib

Summary

Introduction

The first-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) crizotinib has multiple kinase inhibitory activities against ALK, MET, and ROS1, and it shows promising efficacy for non-smallcell lung cancer (NSCLC) patients carrying the ALK gene rearrangement[1,2]. Nextgeneration ALK inhibitors, including alectinib, have high selectivity for ALK, and they have demonstrated. Alectinib demonstrated superior CNS activity versus that of crizotinib in ALK-positive NSCLC patients[6], and it has been approved for the first-line treatment of ALK-positive NSCLC patients. As with crizotinib, acquired resistance remains a limitation of its efficacy[7]. Hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been reported to be involved in acquired resistance to various TKIs and have been seen as critical targets in cancer therapy[8,9]. Studies have found that the abnormal expression of HGF and MET are substantially more frequent in ALKpositive patients than in ALK-negative patients[10], which

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