Multiple myeloma: Combination therapy of BET proteolysis targeting chimeric molecule with CDK9 inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Cyclin Dependent Kinase 9 (CDK9) is crucial for transcriptional elongation, often dysregulated in cancers.
• Bromodomain and Extra-Terminal Domain (BET) proteins are key regulators of gene expression and therapeutic targets in multiple myeloma (MM).

Purpose of the Study:

• To investigate the therapeutic potential of selective CDK9 inhibitors in combination with a BET proteolysis targeting chimeric molecule (PROTAC) against human multiple myeloma cells.
• To evaluate the synergistic effects of combining a CDK9 inhibitor with a BET degrader on MM cell viability, protein expression, and apoptosis.

Main Methods:

• Utilized short-hairpin RNA (shRNA) to silence CDK9 in MM cell lines.
• Administered selective CDK9 inhibitors (AZD 4573) and a BET PROTAC (ARV 825) as single agents and in combination.
• Assessed protein expression of BRD2, BRD4, MYC, and phosphorylated RNA polymerase II (RNAP II).
• Evaluated synergistic effects on cell viability, apoptosis, and in vivo efficacy in preclinical models.

Main Results:

• CDK9 silencing reduced MM cell viability, confirming MM cell dependency on CDK9.
• Combination treatment with ARV 825 and AZD 4573 significantly downregulated BRD2, BRD4, MYC, and phosphorylated RNAP II.
• The combination therapy demonstrated synergistic inhibition of MM cells in vitro and in vivo with minimal toxicity.
• Combination treatment led to a marked increase in apoptotic cells at low doses compared to single agents.

Conclusions:

• The combination of a BET PROTAC (ARV 825) and a CDK9 inhibitor (AZD 4573) represents a novel and effective therapeutic strategy for multiple myeloma.
• This combination targets key pathways involved in MM pathogenesis, offering a promising approach for overcoming therapeutic resistance.