Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Multiple myeloma (MM) is a relapsed and refractory cancer requiring novel therapies to overcome drug resistance.
• Histone deacetylase (HDAC) inhibitors, like panobinostat, combined with bortezomib and dexamethasone, show improved progression-free survival (PFS) in relapsed/refractory MM.
• Calcineurin plays a role in myeloma cell growth and drug resistance, with its catalytic subunit (PPP3CA) mRNA elevated in advanced MM patients.

Purpose of the Study:

• To investigate the role of calcineurin in multiple myeloma cell growth and drug resistance.
• To evaluate the efficacy of targeting calcineurin with HDAC inhibitors and FK506 in MM.
• To explore the potential of calcineurin-targeted therapy for bortezomib-resistant MM.

Main Methods:

• Analyzing mRNA expression of PPP3CA in MM patients.
• Investigating the effect of panobinostat on PPP3CA degradation, potentially mediated by heat shock protein 90 (HSP90) inhibition.
• Assessing the in vitro and in vivo antimyeloma effects of cotreatment with HDAC inhibitors and FK506.
• Evaluating the impact of combination therapy on osteoclast formation.
• Examining the synergistic effects of bortezomib and HDAC inhibitors on MM cell viability via PPP3CA inhibition.

Main Results:

• Panobinostat degrades PPP3CA, a process potentially linked to HSP90 inhibition.
• Cotreatment with HDAC inhibitors and FK506 demonstrated enhanced antimyeloma activity and greater PPP3CA reduction compared to HDAC inhibitors alone, both in vitro and in vivo.
• Combination therapy effectively inhibited osteoclast formation, thereby reducing osteolytic lesions.
• High PPP3CA expression correlated with poor response and short PFS in patients receiving bortezomib-containing therapies, suggesting a role in bortezomib resistance.
• Bortezomib and HDAC inhibitors exhibited synergistic suppression of MM cell viability through PPP3CA inhibition.

Conclusions:

• Calcineurin is a viable therapeutic target in multiple myeloma.
• Combination therapy involving HDAC inhibitors and FK506 shows promise for treating MM, including bortezomib-resistant cases.
• Targeting calcineurin offers a strategy to overcome drug resistance and mitigate osteolytic bone disease in MM patients.