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

Carly Roleder1, Xiaofan Zhao2,3, Vi Lam1

  • 1City of Hope National Medical Center , Duarte, California.

Cancer Research Communications
|April 28, 2026
PubMed

Insights

Resistance to Bruton tyrosine kinase inhibitors (BTKi) is common in mantle cell lymphoma (MCL). A CDK9 inhibitor, AZD4573, showed activity against resistant MCL, but co-targeting oxidative phosphorylation (OxPhos) may enhance efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Bruton tyrosine kinase inhibitors (BTKi) resistance is a significant challenge in mantle cell lymphoma (MCL) treatment.
  • Cyclin-dependent kinase-9 (CDK9) is a crucial regulator of oncogenic transcription and a potential therapeutic target in MCL.

Purpose of the Study:

  • To investigate the efficacy of the selective CDK9 inhibitor AZD4573 in mantle cell lymphoma (MCL), particularly in models resistant to ibrutinib.
  • To explore the impact of CDK9 inhibition on cellular metabolism, including oxidative phosphorylation (OxPhos), and its potential for combination therapy.

Main Methods:

  • Treatment of parental and ibrutinib-resistant MCL cell lines and primary cells with AZD4573.
  • Assessment of cell growth, gene expression (MYC, MCL1), oxygen consumption, ATP production, and reactive oxygen species.
  • Evaluation of AZD4573 in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model.
  • Single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs) from patients treated with AZD4573.
  • In vitro synergy testing of AZD4573 with an OxPhos inhibitor (IACS-010759).

Main Results:

  • AZD4573 inhibited MCL cell growth and downregulated MYC and MCL1 expression.
  • CDK9 inhibition led to increased oxidative phosphorylation (OxPhos), ATP, and reactive oxygen species in resistant MCL cells, suggesting metabolic reprogramming.
  • AZD4573 showed modest survival benefit in a resistant MCL mouse model, with altered signaling pathways and upregulated OxPhos.
  • Clinical data revealed MYC target and OxPhos downregulation in a responding patient, contrasting with upregulation in refractory patients.
  • AZD4573 demonstrated in vitro synergy with the OxPhos inhibitor IACS-010759.

Conclusions:

  • CDK9 inhibition demonstrates therapeutic potential in ibrutinib-resistant mantle cell lymphoma (MCL).
  • Tumor metabolic reprogramming, specifically the upregulation of oxidative phosphorylation (OxPhos), is a key mechanism associated with resistance.
  • Combination therapy targeting both CDK9 and OxPhos presents a promising strategy to overcome resistance in MCL.

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