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<p>Non-small cell lung cancer (NSCLC) with <i>KRAS</i><sup><i>G12C</i></sup> mutation is associated with poor prognosis and resistance to standard therapies. Sotorasib, a <i>KRAS</i><sup>G12C</sup> tyrosine kinase inhibitor, has shown clinical efficacy, yet its interaction with different irradiation modalities remains unclear. This study aimed to evaluate the potential radiosensitizing effect of Sotorasib in such mutated cells exposed to X-rays or carbon-ion (C-ions) irradiation. Two human NSCLC cell lines (H358, <i>KRAS</i><sup>G12C</sup>; and A549, <i>KRAS</i><sup>G12S</sup>) were treated with Sotorasib alone or in combination with X-rays or C-ions irradiation (1–8&#xa0;Gy). Cell viability, clonogenic survival, and sphere-forming ability and cytokines were assessed. Sotorasib alone specifically reduced the clonogenic capacity of H358 cells to ~ 30% while no effect was observed with A549 cells. Interestingly, Sotorasib combined with X-ray irradiation decreased clonogenic survival compared with either treatment alone, without evidence of synergy. In contrast, a synergistic effect was observed with C-ions in H358 cells (β = −0.36, 95% CI [− 0.52 to − 0.20], <i>p</i> &lt; 0.001; enhancement ratio = 4.21 at SF2). C-ions irradiation alone markedly reduced sphere formation in both cell lines, whereas sotorasib showed no additional impact. GM-CSF expression was downregulated with sotorasib alone while IP-10 was upregulated when H358 cells were irradiated with sotorasib, suggesting an immune-specific modulatory response. A specific radiosensitization of <i>KRAS</i><sup>G12C</sup> –mutated NSCLC cells was observed when associating Sotorasib with C-ions. This represents the first evidence of synergistic enhanced cytotoxicity from combining <i>KRAS</i><sup><i>G12C</i></sup> inhibition with high-LET radiation. These findings support further in vivo and translational studies exploring C-ions therapy as a promising strategy for <i>KRAS</i><sup><i>G12C</i></sup>–mutated NSCLC.</p>

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Radio-sensitization of mutated KRAS G12C non-small cell lung cancer with KRAS G12C tyrosine kinase inhibitor and carbon ions irradiation

  • 期刊论文

  • 发表日期：

    2026年7月31日

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  • Mathieu Césaire,
  • Kilian Lecrosnier,
  • Juliette Montanari,
  • Mateusz Sitarz,
  • Sahra Messaoudi,
  • Elisabeth Chartier-Garcia,
  • Isabelle Testard,
  • Guénaëlle Levallet,
  • François Christy,
  • Serge Candéias,
  • François Chevalier

摘要

Non-small cell lung cancer (NSCLC) with KRASG12C mutation is associated with poor prognosis and resistance to standard therapies. Sotorasib, a KRASG12C tyrosine kinase inhibitor, has shown clinical efficacy, yet its interaction with different irradiation modalities remains unclear. This study aimed to evaluate the potential radiosensitizing effect of Sotorasib in such mutated cells exposed to X-rays or carbon-ion (C-ions) irradiation. Two human NSCLC cell lines (H358, KRASG12C; and A549, KRASG12S) were treated with Sotorasib alone or in combination with X-rays or C-ions irradiation (1–8 Gy). Cell viability, clonogenic survival, and sphere-forming ability and cytokines were assessed. Sotorasib alone specifically reduced the clonogenic capacity of H358 cells to ~ 30% while no effect was observed with A549 cells. Interestingly, Sotorasib combined with X-ray irradiation decreased clonogenic survival compared with either treatment alone, without evidence of synergy. In contrast, a synergistic effect was observed with C-ions in H358 cells (β = −0.36, 95% CI [− 0.52 to − 0.20], p < 0.001; enhancement ratio = 4.21 at SF2). C-ions irradiation alone markedly reduced sphere formation in both cell lines, whereas sotorasib showed no additional impact. GM-CSF expression was downregulated with sotorasib alone while IP-10 was upregulated when H358 cells were irradiated with sotorasib, suggesting an immune-specific modulatory response. A specific radiosensitization of KRASG12C –mutated NSCLC cells was observed when associating Sotorasib with C-ions. This represents the first evidence of synergistic enhanced cytotoxicity from combining KRASG12C inhibition with high-LET radiation. These findings support further in vivo and translational studies exploring C-ions therapy as a promising strategy for KRASG12C–mutated NSCLC.