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CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in KIT $D816V^{+}$ Neoplastic Mast Cells
| Content Provider | MDPI |
|---|---|
| Author | Schneeweiss-Gleixner, Mathias Filik, Yüksel Stefanzl, Gabriele Berger, Daniela Sadovnik, Irina Bauer, Karin Smiljkovic, Dubravka Eisenwort, Gregor Witzeneder, Nadine Greiner, Georg Hoermann, Gregor Schiefer, Ana-Iris Schwaab, Juliana Jawhar, Mohamad Reiter, Andreas Sperr, Wolfgang R. Arock, Michel Valent, Peter Gleixner, Karoline V. |
| Copyright Year | 2022 |
| Description | 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. |
| Starting Page | 3070 |
| e-ISSN | 20726694 |
| DOI | 10.3390/cancers14133070 |
| Journal | Cancers |
| Issue Number | 13 |
| Volume Number | 14 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2022-06-23 |
| Access Restriction | Open |
| Subject Keyword | Cancers Oncology Systemic Mastocytosis Kit D816v Midostaurin Avapritinib Cdk4/cdk6 Palbociclib Ribociclib Abemaciclib Targeted Therapy Drug-combinations |
| Content Type | Text |
| Resource Type | Article |
