Abstract 602: Targeting CDK9 with a novel potent and selective inhibitor, YX0798, in CAR-T-relapsed mantle cell lymphoma models

Abstract

Abstract Introduction: Cyclin-dependent kinase (CDK) family members play critical roles in multiple cellular processes. CDK9 is a central regulator at several stages of PolII transcription, including initiation, elongation, and termination. CDK9 dysfunction resulted in transcriptomic reprogramming and promotion of the development of cancers, including lymphoma and leukemia. We and others reported that transcriptomic reprogramming is associated with disease progression and therapeutic resistance in mantle cell lymphoma (MCL). Targeting CDK9 with its inhibitors AZD4573 and enitociclib is safe and effective for treatment in preclinical MCL models, and they are currently under clinical investigation to assess their efficacy and safety. The data demonstrated that CDK9 is a promising therapeutic target. In this study, we developed a novel CDK9 inhibitor, YX0798, and assessed its potency and safety in preclinical MCL models. Method: Cell viability assays were conducted in a time- and dose-dependent manner to assess the in vitro efficacy of YX0798 as well as AZD4573. Apoptosis assays and western blots were used to determine the mechanism of action in MCL cells. Patient-derived xenograft models from primary MCL patient samples were established in immunodeficient mice and used to determine the therapeutic potential YX0798. Results: Next generation sequencing showed that CDK9 was upregulated and cancer hallmarks MYC-TARGETS-v1 and -v2 were highly enriched in CAR-T-relapsed MCL patients compared to CAR-T-naïve patients. We hypothesized that CDK9 overexpression and activity may greatly contribute to the enrichment of MYC-TARGETS-v1 and -v2 in patients with CAR-T resistance, so targeting CDK9 may overcome that resistance. YX0798 was developed to be a potent and selective CDK9 inhibitor. It markedly inhibited cell viability and induced robust apoptosis in MCL cell lines. As expected, it inhibited CDK9 kinase activity and suppressed the expression of short-lived proteins like c-MYC and MCL-1 that are critical for MCL cell survival and growth. YX0798 at 2 mg/kg for continuous 7 days via pump or at 5 mg/kg daily by oral administration potently inhibited the tumor growth of xenografts derived from a patient with therapeutic relapse to the CAR-T therapy in vivo (P<0.0001). This treatment efficacy was found to be similar at that of AZD4573 but at a higher dosage (15+15 mg/kg, 2 hours split, QW, IP). No adverse effects in mice were observed for any of treatments. Conclusion: These data show that our novel CDK9 inhibitor YX0798 is potent and efficacious in treating aggressive MCL models and overcame CAR-T resistance at a lower dosage than AZD4573. Citation Format: Vivian Jiang, Yu Xue, Hong Kim, Joseph McIntosh, Haiying Chen, Tianci Zhang, Yang Liu, Jia Zhou, Michael Wang. Targeting CDK9 with a novel potent and selective inhibitor, YX0798, in CAR-T-relapsed mantle cell lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 602.