Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
Massimo MoroMarina C Garassino

Abstract

We hypothesized that activating KRAS mutations and inactivation of the liver kinase B1 (LKB1) oncosuppressor can cooperate to sustain NSCLC aggressiveness. We also hypothesized that the growth advantage of KRAS/LKB1 co-mutated tumors could be balanced by higher sensitivity to metabolic stress conditions, such as metformin treatment, thus revealing new strategies to target this aggressive NSCLC subtype. We retrospectively determined the frequency and prognostic value of KRAS/LKB1 co-mutations in tissue specimens from NSCLC patients enrolled in the TAILOR trial. We generated stable LKB1 knockdown and LKB1-overexpressing isogenic H1299 and A549 cell variants, respectively, to test the in vitro efficacy of metformin. We also investigated the effect of metformin on cisplatin-resistant CD133+ cells in NSCLC patient-derived xenografts. We found a trend towards worse overall survival in patients with KRAS/LKB1 co-mutated tumors as compared to KRAS-mutated ones (hazard ratio: 2.02, 95% confidence interval: 0.94-4.35, p = 0.072). In preclinical experiments, metformin produced pro-apoptotic effects and enhanced cisplatin anticancer activity specifically in KRAS/LKB1 co-mutated patient-derived xenografts. Moreover, metformin prevented the ...Continue Reading

Citations

Apr 19, 2019·International Journal of Molecular Sciences·Laura BonannoStefano Indraccolo
Nov 30, 2019·Oxidative Medicine and Cellular Longevity·Francesco CiccareseStefano Indraccolo
Oct 31, 2020·Cellular Oncology (Dordrecht)·Ali Fatehi Hassanabad, Kelsey T MacQueen
Dec 15, 2020·European Journal of Pharmacology·Milad AshrafizadehMasoud Najafi
May 22, 2020·The Science of the Total Environment·Bin WangSai-Jun Fan
Jan 10, 2020·Experimental and Molecular Pathology·Hua GuoRui Liu
Mar 5, 2021·Biochemical and Biophysical Research Communications·Shi-Hua DengYing Xu
Apr 23, 2021·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Cristina BorziMassimo Moro
May 29, 2021·BMC Cancer·Felix B MeyerRené Thierbach
Jun 3, 2021·International Journal of Molecular Sciences·Magdalena Markowicz-PiaseckaKristiina M Huttunen
Aug 5, 2021·Expert Opinion on Drug Metabolism & Toxicology·Gerhard Hamilton, Adelina Plangger
Aug 22, 2021·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Colin R LindsayJulien Mazières
Aug 25, 2021·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Cristina BorziMassimo Moro

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