CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in KIT D816V(+) Neoplastic Mast Cells

SIMPLE SUMMARY: Advanced systemic mastocytosis (AdvSM) is a rare malignant disease with a poor prognosis due to the drug resistance of neoplastic mast cells. We found that drugs targeting the cell cycle regulators CDK4 and CDK6 profoundly suppress the growth and survival of neoplastic mast cells. Furthermore, these drugs can overcome resistance against KIT D816V-targeting drugs, including midostaurin, in neoplastic mast cells. Finally, the CDK4/CDK6 inhibitors applied induced apoptosis in CD34+/CD38− stem cells in AdvSM. Based on these results, we believe that CDK4/CDK6 inhibition may be a new and interesting therapeutic approach with curative potential for AdvSM. Whether combinations of KIT D816-targeting drugs and CDK4/CDK6 inhibitors can induce long-term remission in patients with AdvSM remains to be determined in clinical trials. ABSTRACT: 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.