Onconova announces preclinical data on narazaciclin in BTKi-resistant MCL

Onconova Therapeutics announced preclinical data, highlighting narazaciclib’s preclinical activity in Bruton’s kinase inhibitor-resistant mantle cell lymphoma, in a poster presented on December 11, 2023 at the 65th Annual Meeting of the American Society for Hematology in San Diego. Poster Highlights: Title: Narazaciclib, a differentiated CDK4/6 antagonist, prolongs cell cycle arrest and metabolomic reprogramming, enabling restoration of ibrutinib sensitivity in BTKi-resistant mantle cell lymphoma: Objectives: To evaluate the activity and mechanism of action of narazaciclib as a single agent and in combination with ibrutinib, in comparison to the standard-of-care ibrutinib, in preclinical models of MCL that are sensitive and resistant to ibrutinib treatment. Snapshot of the Results and Conclusions: Tumor Growth Inhibition: Narazaciclib showed safety and efficacy as a single agent in preclinical MCL models, including ibrutinib-resistant settings, with significant reductions in cell viability. Combination Synergy: The narazaciclib plus ibrutinib combination showed synergy in vitro and in vivo, especially in ibrutinib-resistant models, with overall greater synergy, measured by lower “Combination Index” values, versus ibrutinib-sensitive cells. Cell Cycle Blockade: The combination of narazaciclib plus ibrutinib induces a superior G1 cell cycle blockade in both ibrutinib-sensitive and ibrutinib-resistant MCL cells. Metabolic programming: In ibrutinib-resistant cases, the synergy between narazaciclib and ibrutinib triggers metabolic reprogramming alongside DNA damage, mediated by the USP24 and P53 axis, as evidenced by several assays to assess mitochondrial metabolism. Together, these preclinical data suggest that narazaciclib has important single agent activity and the potential to restore ibrutinib sensitivity in BTKi-resistant models, successfully meeting the primary objective of the study.