Abstract 1127: Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines

Abstract

Abstract KRAS is the most frequently mutated oncogene in lung adenocarcinoma, in which is related to poor treatments response and worse survival rates than other driver mutations. KRAS activates MAPK and mTOR pathways, and even after sotorasib treatment, a novel KRAS inhibitor, the duration of responses to this monotherapy are excessively short. In this context, metformin is able to inhibit PI3K and mTOR pathways; therefore, combined use of metformin with sotorasib aids to diminish the activity of both signaling pathways. We performed a dose-effect curve to determine IC50 of sotorasib, and IC10 of metformin to treat lung cancer cell lines harboring different mutational profiles: A549 (KRAS G12S), and H522 (TP53) in order to study the effects of the combination compared to the monotherapy of each drug at MTT assay and western blot analysis. In detail, we evaluated drug-induced cytotoxicity, apoptosis, and activity of MAPK and mTOR pathways. Our results show a synergic effect in cytotoxicity by MTT assay, as well as increased inhibition of MAPK pathway inhibition at combinational treatment, compared to monotherapies in A549 cell lines; conversely, we did not find significant effects on cytotoxicity and signaling inhibition in H522 cell line. In conclusion, the combined treatment of metformin and sotorasib show synergistic effects in drug-induced cytotoxicity and inhibition of MAPK pathways in lung cancer cell lines. Citation Format: Norma Yanet Hernandez-Pedro, Jose Lucio-Lozada, Pedro Barrios-Bernal, Maritza Ramos-Ramírez, Oscar Arrieta. Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1127.