CDK9 pharmacological inhibition with PRT2527 has antitumor activity in marginal zone lymphoma models and can improve the effects of BTK, PI3K, and BCL2 inhibitors

Abstract Cyclin-dependent kinase 9 (CDK9) drives transcriptional elongation and supports the expression of short-lived oncogenic and anti-apoptotic proteins such as MYC and MCL1. PRT2527 is a potent, selective CDK9 inhibitor currently in early clinical development. We evaluated its preclinical activity in marginal zone lymphoma (MZL) models, including cell lines with acquired resistance to BTK, PI3K, and BCL2 inhibitors. Short exposure (4 hours) to PRT2527 produced nanomolar cytotoxicity across all tested MZL cell lines, with efficacy maintained in resistant derivatives. Transcriptomic profiling of VL51 cells showed broad gene repression, including MYC, IRF4, NF-κB-related genes, and MCL1, alongside increased expression of HLA class II genes. Moreover, comparison with additional CDK inhibitors revealed a similar transcriptional repression signature, underscoring a conserved CDK-dependent regulatory network. Protein analyses confirmed rapid depletion of MCL1, MYC, RNA polymerase II, and IRF4. Flow cytometry validated increased HLA class II and decreased HLA class I surface expression. Combination studies demonstrated additive to synergistic effects with BTK inhibition (ibrutinib) or dual PI3K/BCL2 inhibition (copanlisib plus venetoclax), independent of baseline drug sensitivity. Mechanistically, these combinations may enhance apoptosis by concurrently suppressing survival signaling and transcriptional addiction. Analysis of patient samples revealed high CDK9 expression, further supporting the biological relevance and therapeutic rationale for targeting CDK9 in this disease. Our findings support the development of CDK9-based combination strategies for relapsed/refractory MZL and other B-cell malignancies, with an additional potential for integration with immunotherapies. Key Points CDK9 inhibitor PRT2527 kills marginal zone lymphoma cells, regardless of whether they are resistant to other targeted drugs. PRT2527 boosts the effects of BTK, PI3K, and BCL2 inhibitors and alters immune-related gene expression. Competing Interest Statement Potential Competing Interests Alberto J. Arribas: travel grant from AstraZeneca and Floratek Pharma, advisory board fee from PentixaPharm. Luciano Cascione: institutional research funds from Orion; travel grant from HTG. Davide Rossi: grant support from Gilead, AbbVie, Janssen; honoraria from Gilead, AbbVie Janssen, Roche; scientific advisory board fees from Gilead, AbbVie, Janssen, AstraZeneca, MSD. Anastasios Stathis: institutional research funds from Pfizer, MSD; Roche, Novartis, Amgen, Abbvie, Bayer, ADC Therapeutics, MEI Therapeutics, Philogen, Celestia. Astra Zeneca; travel grant from AbbVie and PharmaMar; consulting fee paid to institution from Jansen, Roche, Eli Lilly. Diane Heiser: Prelude employment Francesco Bertoni: institutional research funds from ADC Therapeutics, Bayer AG, BeiGene, Floratek Pharma, Helsinn, HTG Molecular Diagnostics, Ideogen AG, Idorsia Pharmaceuticals Ltd., Immagene, ImmunoGen, iOnctura, Mabtree, Menarini Ricerche, Nordic Nanovector ASA, Oncternal Therapeutics, Spexis AG; consultancy fee from BIMINI Biotech, Floratek Pharma, Helsinn, Immagene, Menarini, Vrise Therapeutics; advisory board fees to institution from Novartis; travel grants from Amgen, Astra Zeneca, iOnctura. The other Authors have nothing to disclose.