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ORIGINAL RESEARCH article

Front. Oncol.

Sec. Cancer Molecular Targets and Therapeutics

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1654491

This article is part of the Research TopicInnovative Drug Combinations for Enhanced Solid Tumor Treatment EfficacyView all 10 articles

KRAS G12C inhibition enhances efficacy to conventional chemotherapy in KRAS-mutant NSCLC

Provisionally accepted
Alessandro TubitaAlessandro Tubita1Sara FancelliSara Fancelli2Lorenzo AnelaLorenzo Anela1Giulia PetroniGiulia Petroni1Enrico CalimanEnrico Caliman2Francesca MazzoniFrancesca Mazzoni2Federico ScolariFederico Scolari3Brunella NapolitanoBrunella Napolitano2Beatrice MenicacciBeatrice Menicacci4Camilla Eva CominCamilla Eva Comin1Luca VoltoliniLuca Voltolini1Serena PillozziSerena Pillozzi3*Lorenzo AntonuzzoLorenzo Antonuzzo1
  • 1Universita degli Studi di Firenze Dipartimento di Medicina Sperimentale e Clinica, Florence, Italy
  • 2Azienda Ospedaliero Universitaria Careggi Centro Oncologico di Riferimento Dipartimentale, Florence, Italy
  • 3Universita degli Studi di Firenze Dipartimento di Scienze Biomediche Sperimentali e Cliniche Mario Serio, Florence, Italy
  • 4Universita degli Studi di Firenze Dipartimento di Scienze della Salute, Florence, Italy

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Despite recent therapeutic advances, the adjuvant treatment of non-small cell lung cancer (NSCLC) remains a challenge. Reducing the risk of recurrence is still a concern, especially in the KRAS G12C population, for which platinum-based adjuvant chemotherapy (CT) remains the gold standard. In this study, we evaluated the efficacy, in terms of cell viability and volumetric reduction, of adding KRAS inhibitors (KRASi) sequentially or concurrently to CT in both parental (PR) and gemcitabine-resistant (GR) KRAS mutated NSCLC cell lines (SW1573 and H23). We demonstrated that KRASi added to CT (both sequential and concurrent treatment strategies) reduced cell viability in SW1573-PR and H23-PR and this effect is less evident in GR cell lines. Interestingly, in the 3D model, the concomitant use of KRASi+CT reduced spheroid volume in both PR and GR spheroids. Our results indicate that KRASi enhances the efficacy of CT in both NSCLC PR and GR cells, suggesting a potential therapeutic strategy to overcome chemoresistance in the adjuvant setting of NSCLC.

Keywords: NSCLC, KRAS mutations, chemoresistance, KRAS inhibitors (KRASi), Adjuvant chemotherapy

Received: 26 Jun 2025; Accepted: 26 Aug 2025.

Copyright: © 2025 Tubita, Fancelli, Anela, Petroni, Caliman, Mazzoni, Scolari, Napolitano, Menicacci, Comin, Voltolini, Pillozzi and Antonuzzo. 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: Serena Pillozzi, Universita degli Studi di Firenze Dipartimento di Scienze Biomediche Sperimentali e Cliniche Mario Serio, Florence, Italy

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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