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Abstract
Introduction. KRAS mutations are identified in approximately 15–30% of lung adenocarcinomas. However, developing effective targeted therapies for this major subset of lung cancer has remained challenging, with the exception of tumors with the KRAS p.G12C mutation. Inhibition of MEK kinase, a key component of the RAS-driven signaling cascade, represents a promising therapeutic strategy for these tumors. Nevertheless, MEK inhibitor monotherapy has shown limited efficacy, as cancer cells adapt to this intervention by activating autophagy.
Aim. To investigate the efficacy of combining the MEK inhibitor trametinib with the autophagy inhibitor hydroxychloroquine for treating non-small cell lung cancer (NSCLC) harboring KRAS mutations, using a patient-derived explant culture model.
Materials and Methods. The study utilized tissue samples from 38 chemo-naive, surgically resected lung carcinomas. Tumor explants generated from this material were incubated for 48 hours in a culture medium supplemented with trametinib and/or hydroxychloroquine at various concentrations. Treatment efficacy was assessed via immunohistochemical (IHC) analysis of phosphorylated ERK levels, reflecting MEK kinase activity, and caspase-3 levels, as a marker of apoptosis. Based on morphological assessment of explant viability and quality, 21 samples were included in the final drug sensitivity analysis, six of which carried KRAS mutations.
Results. A significant decrease in p-ERK levels was observed across the entire sample cohort following treatment with the combination of trametinib (20 µM) and hydroxychloroquine (25 µM) (p = 0.005). This suppressive effect was more pronounced in explants with KRAS mutations (p = 0.006) compared to tumors without mutations or with other genetic driver events. No significant changes in the expression of the apoptosis marker c-Casp3 were detected.
Conclusion. The combination of trametinib and hydroxychloroquine effectively reduces MEK kinase activity in lung tumor cells with KRAS mutations.
References
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