Cyclin-dependent kinase-9 and oxidative phosphorylation inhibition overcome ibrutinib resistance in mantle cell lymphoma

Resistance to Bruton tyrosine kinase inhibitors (BTKi) is inevitable in mantle cell lymphoma (MCL). Cyclin-dependent kinase-9 (CDK9), a key regulator of oncogenic transcription, is a promising therapeutic target. Here we studied a selective CDK9 inhibitor, AZD4573, in MCL. AZD4573 suppressed growth of MCL cell lines and primary cells and reduced expression of key oncogenic programs including MYC and MCL1. However, CDK9 inhibition also induced metabolic adaptation, with increased oxidative phosphorylation (OxPhos), ATP production, and reactive oxygen species in ibrutinib-resistant models. In an ibrutinib-resistant MCL PDX model, AZD4573 produced modest survival benefit and suppressed TNFα/NF-κB and mTORC1 signaling, but OxPhos remained elevated. To define treatment-associated transcriptional changes at cellular resolution, we analyzed PBMCs from patients receiving AZD4573 using single-cell RNA sequencing. In a responding MCL patient, malignant B cells showed sustained downregulation of MYC targets and OxPhos, whereas refractory patients showed the opposite pattern, with upregulation of MYC-associated and OxPhos programs. Consistent with these findings, the OxPhos inhibitor IACS-010759 synergized with AZD4573 in vitro. Together, these results support CDK9 inhibition as a therapeutic strategy in BTKi-resistant MCL and highlight single-cell transcriptomics as a powerful approach to reveal response-associated malignant cell states and rational combination vulnerabilities.