Cyclin-Dependent Kinase-9 and Oxidative Phosphorylation Inhibition Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma.

Resistance to Bruton tyrosine kinase inhibitors is inevitable in mantle cell lymphoma (MCL). Cyclin-dependent kinase-9 (CDK9), a key regulator of oncogenic transcription, is a promising therapeutic target. In this study, we studied a selective CDK9 inhibitor, AZD4573, in MCL. Treatment with AZD4573 thwarted growth of both parental and ibrutinib-resistant MCL cell lines and primary MCL cells and downregulated expression of MYC and MCL1. However, CDK9 inhibition enhanced basal and maximal oxygen consumption rate, as well as increased production of ATP and reactive oxygen species in ibrutinib-resistant cell lines and primary MCL cells. Whereas treatment with AZD4573 led to modest prolongation of survival in an ibrutinib-resistant MCL patient-derived xenograft mouse model, accompanied by downregulation of TNFα/NF-κB and mTORC1 signaling pathways in murine splenocytes, oxidative phosphorylation (OxPhos) was upregulated, suggesting tumor metabolic reprogramming. Single-cell RNA sequencing analysis of peripheral blood mononuclear cells (PBMC) from patients treated with AZD4573 on a clinical trial demonstrated sustained downregulation of MYC targets and OxPhos in malignant B cells from a responding patient with MCL. Conversely, two refractory patients exhibited upregulation of MYC targets and OxPhos in PBMCs. OxPhos inhibitor IACS-010759 demonstrated synergy with AZD4573 in vitro. Thus, CDK9 inhibition exhibits activity in ibrutinib-resistant MCL and can be further enhanced by cotargeting of OxPhos. SIGNIFICANCE: Ibrutinib resistance is a challenge in MCL. Targeting CDK9 partially overcomes this resistance but results in upregulation of cell metabolism contributing to survival. Dual targeting of CDK9 and OxPhos cooperates to suppress tumor growth, providing a rationale for future exploration of combination therapies in MCL.