Abstract 1078: Sotorasib and metformin combination enhances cytotoxicity and apoptosis in KRAS mutant lung cancer cell lines

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.1078-1078
• Main Authors: Hernandez-Pedro, Norma Yanet, Barrios-Bernal, Pedro, Lucio-Lozada, José, Ramos-Ramirez, Maritza, Arrieta, Oscar
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-1078

KRAS is the most frequently mutated oncogene in lung adenocarcinoma (50%) and it is associated with a poor response to antineoplastic treatments, as well as poorer survival rates. KRAS activates the MAPK pathway, promoting cell survival and increasing protein synthesis. Novel inhibitors of KRAS G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to avoid this inconvenience by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the mTOR pathway in lung cancer cell lines with or without KRAS mutations. Methods: We performed dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin. Then, these doses were used to treat lung cancer cell lines A549 (KRAS G12S), H522 (without KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by MTT assay, apoptosis induction through flow cytometry with Annexin V and 7AAD, and the activity of P70S6K and AKT proteins by western blot. Main outcomes and measures: cell survival, apoptosis, expression, and phosphorylation of intermediaries belonging to the mTOR pathway. Results: The combined treatment showed a synergic effect on cytotoxicity, increased apoptosis induction, and notable inhibition of AKT and P70S6K1 proteins, compared to sotorasib alone or to control groups in all the cell lines, but predominantly in KRAS-mutated cells (H23 and A549). Conclusions: The combination of metformin with sotorasib showed synergic effects on cytotoxicity, increased apoptosis induction, and a remarkable inhibition of downstream proteins involved in the signaling of growth factor receptors in all tested cells. Moreover, these results suggest a sensitizing effect of metformin to sotorasib treatment in cells without KRAS mutations, such as H522. Citation Format: Norma Yanet Hernandez-Pedro, Pedro Barrios-Bernal, José Lucio-Lozada, Maritza Ramos-Ramirez, Oscar Arrieta. Sotorasib and metformin combination enhances cytotoxicity and apoptosis in KRAS mutant lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1078.