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. 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. While treatment with AZD4573 led to modest prolongation of survival in an ibrutinib-resistant MCL PDX mouse model, accompanied by downregulation of TNF/NF-B and mTORC1 signaling pathways in murine splenocytes, OxPhos was upregulated suggesting tumor metabolic reprogramming. Single-cell RNA Sequencing analysis of PBMCs 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 co-targeting of OxPhos.