The effect of metformin in EML4-ALK+ lung cancer alone and in combination with crizotinib in cell and rodent models

Cell based studies have suggested that the diabetes drug metformin may combine with the anaplastic lymphoma kinase receptor (ALK) inhibitor crizotinib to increase ALK positive lung cancer cell killing and overcome crizotinib resistance. We therefore tested metformin alone and in combination with crizotinib in vivo, by employing a xenograft mouse model of ALK positive lung cancer. We found that 14 days of daily oral metformin (100 mg/kg) alone had a moderate but statistically significant effect on tumour growth suppression, but in combination with crizotinib, produced no greater tumour suppression than crizotinib (25 mg/kg) alone. We also reassessed the effect of metformin on EML4-ALK positive lung cancer (H3122) cell viability. Although metformin alone did have a moderate effect on cell viability (30% suppression) this was only at a clinically irrelevant concentration (5 mM) and there was no additive effect with cytotoxic concentrations of crizotinib. Moreover, metformin did not overco..... READ ARTICLE

Biochemical Pharmacology DOI:10.1016/j.bcp.2020.114345

Authors: A.R. Bland, N. Shrestha, R.L. Bower, R.J. Rosengren, J.C. Ashton

Pre-ClinicalKirk SmithJanuary 1, 2021Crizotinib, Metformin, EML4-ALK+ lung cancer

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

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 im..... READ ARTICLE

Cell Death & Disease DOI:10.1038/s41419-020-2307-5

Authors: Chen, H., Lin, C., Peng, T. et al.

Pre-ClinicalKirk SmithFebruary 10, 2020Metformin, HGF-induced resistance, alectinib, Gab1