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ORIGINAL RESEARCH article

Front. Mol. Biosci.
Sec. Molecular Diagnostics and Therapeutics
Volume 12 - 2025 | doi: 10.3389/fmolb.2025.1537523

Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-Mediated Signaling

Provisionally accepted
Raquel Arantes Megid Raquel Arantes Megid 1Guilherme Gomes Ribeiro Guilherme Gomes Ribeiro 1Izabela Natalia Faria Gomes Izabela Natalia Faria Gomes 1Ana Carolina Laus Ana Carolina Laus 1Leticia Ferro Leal Leticia Ferro Leal 1,2Luciane Sussuchi Da Silva Luciane Sussuchi Da Silva 1Abu-Bakr Ariwoola Abu-Bakr Ariwoola 1Josiane Mourão Dias Josiane Mourão Dias 1Rui Manuel Reis Rui Manuel Reis 1,3,4Renato Silva-Oliveira Renato Silva-Oliveira 1*
  • 1 Barretos Cancer Hospital, Barretos, Brazil
  • 2 Faculty of Health Sciences of Barretos Dr. Paulo Prata (FACISB), Barretos, Brazil
  • 3 Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Braga, Portugal
  • 4 ICVS/3B’s Associate Laboratory, Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimaraes, Braga, Portugal

The final, formatted version of the article will be published soon.

    The molecular non-genetic changes of resistance to sotorasib are currently uncertain. The aim of this study was to generate a sotorasib-resistant cell line via selective pressure and systematically examine the molecular and phenotypic alterations caused by resistance. Methods: Mutant NCI-H358 (KRAS G12C ) were exposed to incremental doses (2 to 512 nM) of sotorasib. Then, resistant clones were separated by single-cell sorting. Proliferation was analyzed in real-time by xCELLigence; protein profiles were quantified by protein arrays; and mRNA expression profile was measured using the PanCancer Pathways panel by NanoString. In silico analyses were conducted from a database comprising patient-derived xenograft (PDX) models and cell lines resistant to sotorasib. AKT and p38. The synergistic effect of combining AKT, p38, and EGFR inhibitors was assessed using the SynergyFinder platform. Additionally, AKT and p38 genes were silenced using esiRNA Results: Sotorasib-resistant H358-R cell line displayed markers of the mesenchymal-epithelial transition and loss of cell adhesion.Were identified 30 overexpressed genes in the resistance model, implicating in signaling pathways that leads to AKT activation and heightened protein expression levels of phosphorylated AKT and p38. To identify potential therapeutic strategies for overcoming sotorasib resistance, we investigated the combination of AKT and p38 inhibitors.Notably, combined inhibition of AKT (MK2206) and p38 (adezmapimod) restored sensitivity to sotorasib in resistant cell lines, as did silencing AKT expression.Conclusions: These findings underscore the importance of adaptive mechanisms in sotorasib resistance in NSCLC cells contributing by EMT activation and demonstrates synergic combination with AKT and p38 inhibitors to restore sotorasib sensitivity in KRAS G12C cells.

    Keywords: Sotorasib, KRAS, NSCLC, sotorasib-resistant, combination therapy

    Received: 01 Dec 2024; Accepted: 14 Jan 2025.

    Copyright: © 2025 Megid, Ribeiro, Gomes, Laus, Ferro Leal, Sussuchi Da Silva, Ariwoola, Dias, Reis and Silva-Oliveira. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Renato Silva-Oliveira, Barretos Cancer Hospital, Barretos, Brazil

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