CREB Regulates Cisplatin Resistance by Targeting TNKS and KDM6A in NSCLC cell-Derived Tumor Spheroid

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Platinum-based chemotherapy is standard for advanced non-small cell lung cancer (NSCLC).
• Innate and acquired resistance to chemotherapy presents a significant clinical challenge.
• Identifying molecular mechanisms driving resistance is crucial for developing effective treatments.

Purpose of the Study:

• To identify transcriptional regulators involved in cisplatin resistance in non-small cell lung cancer.
• To elucidate the role of cAMP response element-binding protein 1 (CREB) in mediating chemoresistance.
• To explore CREB as a potential therapeutic target for overcoming cisplatin resistance.

Main Methods:

• Classification of NSCLC cell lines into cisplatin-sensitive and -resistant groups using 3D tumor spheroids.
• Reverse engineering and functional validation to identify key regulatory proteins.
• Analysis of CREB occupancy at target gene regulatory regions (TNKS, KDM6A) via ChIP assays.
• Assessment of CREB knockdown effects on cisplatin sensitivity in vitro and in vivo (xenograft mouse model).

Main Results:

• cAMP response element-binding protein 1 (CREB) was identified as a major regulator of cisplatin resistance.
• Cisplatin treatment reduced CREB binding to TNKS and KDM6A regulatory regions in sensitive cells, decreasing their expression.
• CREB knockdown increased cisplatin sensitivity and reduced TNKS and KDM6A levels in resistant NSCLC models.
• CREB inhibition demonstrated efficacy in both tumor spheroids and a xenograft mouse model.

Conclusions:

• CREB plays a critical role in the development of cisplatin resistance in non-small cell lung cancer.
• Targeting CREB, potentially through inhibition, represents a promising therapeutic strategy for patients with cisplatin-resistant NSCLC.
• Understanding CREB's regulatory function provides insights into overcoming chemoresistance mechanisms.