CDK Inhibition in Lung Cancer Alters Epithelial-Mesenchymal Transition, Autophagy, and Metabolism.

Abstract

Introduction: Lung cancer remains the leading cause of cancer-related mortality worldwide, responsible for over 1.8 million deaths annually. Despite therapeutic advancements, clinical outcomes in advanced lung adenocarcinoma (LUAD) remain poor due to treatment resistance and metastasis. Cyclin-dependent kinases (CDKs) are essential regulators of cell cycle progression and transcription, yet their therapeutic targeting-especially beyond CDK4 and CDK6-has been largely underexplored in lung cancer. This study investigates the oncogenic relevance of CDK1, CDK2, CDK5, CDK7, and CDK9 in LUAD and evaluates the effects of two pharmacological CDK inhibitors: Roscovitine (a broad-spectrum CDK inhibitor) and RO-3306 (a CDK1-selective inhibitor).

Methods: Gene expression levels of CDK family members were analyzed using the UALCAN tool, based on the Cancer Genome Atlas (TCGA) LUAD dataset. LUAD cell lines A549 and H292 were treated with Roscovitine and RO-3306 at various concentrations and durations. Cell viability was assessed using the MTT assay; migration was evaluated through wound healing assays. Protein expression of autophagy markers, epithelial-to-mesenchymal transition marker, and metabolic stress markers was assessed by Western blotting.

Results: Bioinformatic analysis revealed significant overexpression of CDK1, CDK2, CDK5, CDK7, and CDK9 in LUAD compared to normal lung tissue. Both inhibitors reduced cell viability in a dose- and time-dependent manner, with Roscovitine demonstrating greater potency. Notably, Roscovitine significantly suppressed cell migration and upregulated E-cadherin expression, suggesting reversal of epithelial-to-mesenchymal transition. Additionally, Roscovitine induced complete autophagic flux, as shown by LC3-II accumulation and p62 degradation, along with activation of metabolic stress pathways. In contrast, RO-3306 selectively impaired migration only in H292 cells and triggered incomplete autophagy, indicating a more limited mechanistic effect.

Discussion: This study identifies CDK1, CDK2, CDK5, CDK7, and CDK9 as overexpressed and actionable targets in LUAD. Importantly, it reveals for the first time that CDK inhibition- particularly via Roscovitine-modulates both cell migration and autophagy through distinct and potent mechanisms.

Conclusion: These findings support the further development of multi-target CDK inhibitors as promising candidates to overcome tumor progression and therapeutic resistance in lung cancer.