Role of KRAS mutation on NSCLC resistance to x-rays and carbon ions

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Césaire, Mathieu | Lecrosnier, Kilian | Gilbert, Antoine | Montanari, Juliette | Chevalier, François

Edité par CCSD -

International audience. Unresectable locally advanced non-small cell lung cancer (NSCLC) is a frequent cancer with a prognosis that remains poor despite several treatments such as radiotherapy, chemotherapy and immunotherapy. Mechanisms of resistance to treatments have been highlighted such as KRAS mutations. A new therapy type tyrosine kinase inhibitor targeting the KRAS G12C mutation has enabled efficacy in metastatic NSCLC and could have an interest in the treatment by radiotherapy locally advanced forms. However, the radiosensitizing effect of such molecules targeting KRAS remains unknown. In this study, we propose to use in vitro models of KRAS G12C mutated cell lines (vs. non-mutated)H358 cells (KRAS G12C mutated) and A549 cells (vs. non-mutated) were treated in vitro with a combination of KRAS G12C inhibitors and irradiations (X-rays or carbon ions). Drug toxicity, clonogenic, cell proliferation, tumorsopheres assays and RTq PCR for cancer stem cells (CSC) markers were performed in both cell lines.Combining sotorasib and irradiation induced less proliferation and less clonogenic survival compared to sotorasib or irradiation alone in H358 cells with an additive effect but no synergistic effect. However, the combination of sotorasib and irradiation induced less CSC formation with a synergistic effect in H358 cells. CSC markers expression was modified by the combination of sotorasib and irradiation in H358 cells.Sotorasib in combination with X-rays irradiation or carbon ions irradiation exerts a toxic effect on H358 cells especially in CSC population.

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