A Novel Combination of Sotorasib and Metformin Enhances Cytotoxicity and Apoptosis in KRAS-Mutated Non-Small Cell Lung Cancer Cell Lines through MAPK and P70S6K Inhibition

• Published in: International journal of molecular sciences Vol. 24; no. 5; p. 4331
• Main Authors: Barrios-Bernal, Pedro, Lucio-Lozada, José, Ramos-Ramírez, Maritza, Hernández-Pedro, Norma, Arrieta, Oscar
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22-02-2023; MDPI
• Subjects: AKT; AKT protein; Antidiabetics; Apoptosis; Cancer therapies; Carcinoma, Non-Small-Cell Lung - genetics; Cell cycle; Cell Line; Cytotoxicity; Drug dosages; Flow cytometry; Flow mapping; Humans; K-Ras protein; Kinases; KRAS; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - metabolism; MAP kinase; MAPK; Metformin; Metformin - pharmacology; Mutation; Non-small cell lung carcinoma; P70S6K; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Sensitizing; sotorasib; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor cell lines; Massachusetts; lung cancer; sotorasib; metformin; AKT; KRAS; MAPK; P70S6K
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24054331

Novel inhibitors of KRAS with 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 break this resistance 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 MAPK and mTOR pathways. We created dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin in three lung cancer cell lines; A549 (KRAS G12S), H522 (wild-type KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by an MTT assay, apoptosis induction through flow cytometry, and MAPK and mTOR pathways were assessed by Western blot. Our results showed a sensitizing effect of metformin on sotorasib effect in cells with KRAS mutations and a slight sensitizing effect in cells without K-RAS mutations. Furthermore, we observed a synergic effect on cytotoxicity and apoptosis induction, as well as a notable inhibition of the MAPK and AKT-mTOR pathways after treatment with the combination, predominantly in KRAS-mutated cells (H23 and A549). The combination of metformin with sotorasib synergistically enhanced cytotoxicity and apoptosis induction in lung cancer cells, regardless of KRAS mutational status.