CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in KIT D816V + Neoplastic Mast Cells.
Mathias Schneeweiss-GleixnerYüksel FilikGabriele StefanzlDaniela BergerIrina SadovnikKarin BauerDubravka SmiljkovicGregor EisenwortNadine WitzenederGeorg GreinerGregor HoermannAna-Iris SchieferJuliana SchwaabMohamad JawharAndreas ReiterWolfgang R SperrMichel ArockPeter ValentKaroline V GleixnerPublished in: Cancers (2022)
In most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express KIT D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. Cyclin-dependent kinase (CDK) 4 and CDK6 are promising targets in oncology. We found that shRNA-mediated knockdown of CDK4 and CDK6 results in growth arrest in the KIT D816V + MC line HMC-1.2. The CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib suppressed the proliferation in primary neoplastic MC as well as in all HMC-1 and ROSA cell subclones that were examined. Abemaciclib was also found to block growth in the drug-resistant MC line MCPV-1, whereas no effects were seen with palbociclib and ribociclib. Anti-proliferative drug effects on MC were accompanied by cell cycle arrest. Furthermore, CDK4/CDK6 inhibitors were found to synergize with the KIT-targeting drugs midostaurin, avapritinib, and nintedanib in inducing growth inhibition and apoptosis in neoplastic MCs. Finally, we found that CDK4/CDK6 inhibitors induce apoptosis in CD34+/CD38- stem cells in AdvSM. Together, CDK4/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM. Whether CDK4/CDK6 inhibitors can improve clinical outcomes in patients with AdvSM remains to be determined in clinical trials.
Keyphrases
- cell cycle
- cell cycle arrest
- stem cells
- cell proliferation
- drug resistant
- cell death
- clinical trial
- oxidative stress
- end stage renal disease
- palliative care
- emergency department
- chronic kidney disease
- cystic fibrosis
- cell therapy
- rheumatoid arthritis
- prognostic factors
- single cell
- peritoneal dialysis
- protein kinase
- patient reported outcomes
- human health