Researchers discovered that compounds targeting cyclin-dependent kinase (CDK) 4 and CDK6 suppressed the neoplastic mast cell (MC) growth found in systemic mastocytosis (SM) and published their results in Cancers. They noted that it remains to be determined whether combinations of CDK4/CDK6 inhibitors and KIT D816-targeting drugs would be able to induce remission in patients with advanced SM.

“Recent pre-clinical studies have shown promising effects of CDK4/CDK6 inhibitors in certain hematologic malignancies,” the authors wrote. “In the current study, we explored the expression and role of CDK4/CDK6 in neoplastic MC and evaluated the anti-neoplastic effects of CDK4/CDK6-targeting drugs alone or in combination with KIT D816V-targeting [tyrosine kinase inhibitor].”

Read more about SM experimental therapies

Although KIT-targeting drugs have been shown to reduce the MC burden in patients with advanced SM, long-lasting remissions remain elusive. Here, the authors assessed the potential of CDK4/CDK6 inhibitors, which are already established as effective in breast cancer, as an alternative targeted treatment in the context of SM.

After confirming that CDK4 and CDK6 were expressed in the neoplastic cells of patients with SM, the team demonstrated the ability of palbociclib, ribociclib, and abemaciclib, 3 US Food and Drug Administration-approved CDK4/CDK6 inhibitors, to consistently block MCL-like cell and neoplastic cell proliferation and induce cell cycle arrest. In addition, the inhibitors also sensitized neoplastic MC to midostaurin, avaprotinib, and nintedanib.

Given that palbociclib, ribociclib, and abemaciclib are approved and are generally well-tolerated by patients as single agents, the authors suggest the possibility of their use in patients who have developed resistance to midostaurin. Furthermore, the combination of a CDK4/CDK6 inhibitor with 1 of the 3 drugs might carry a more powerful anticancer effect than their use alone—a concept that will require assessment in upcoming clinical trials.

Reference

Schneeweiss-Gleixner M, Filik Y, Stefanzl G, et al. CDK4/CDK6 inhibitors synergize with midostaurin, avapritinib, and nintedanib in inducing growth inhibition in KIT D816V+ neoplastic mast cells. Cancers. Published online June 23, 2022. doi:10.3390/cancers14133070