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Response and resistance to CDK12 inhibition in aggressive B-cell lymphomas
Jing Gao1, Michelle Y Wang1, Yuan Ren1
1Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612.
Abstract:
Despite significant progress in the treatment of patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), the prognosis of patients with relapsed disease remains poor due to the emergence of drug resistance and subsequent disease progression. Identification of novel targets and therapeutic strategies for these diseases represents an urgent need. Here, we report that both MCL and DLBCL are exquisitely sensitive to transcription-targeting drugs, in particular THZ531, a covalent inhibitor of cyclin-dependent kinase 12 (CDK12). By implementing pharmacogenomics and a cell-based drug screen, we found that THZ531 leads to inhibition of oncogenic transcriptional programs, especially the DNA damage response pathway, MYC target genes and the mTOR-4EBP1-MCL-1 axis, contributing to dramatic lymphoma suppression in vitro. We also identified de novo and established acquired THZ531-resistant lymphoma cells conferred by over-activation of the MEK-ERK and PI3K-AKT-mTOR pathways and upregulation of multidrug resistance-1 (MDR1) protein. Of note, EZH2 inhibitors reversed resistance to THZ531 by competitive inhibition of MDR1 and, in combination with THZ531, synergistically inhibited MCL and DLBCL growth in vitro. Our study indicates that CDK12 inhibitors, alone or together with EZH2 inhibitors, offer promise as novel effective approaches for difficult-to-treat DLBCL and MCL.
Insights
Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) show sensitivity to CDK12 inhibitors like THZ531, offering new therapeutic avenues. EZH2 inhibitors can overcome resistance, suggesting combination therapy for relapsed lymphomas.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Relapsed diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) have poor prognoses due to drug resistance.
- Novel therapeutic targets and strategies are urgently needed for these aggressive lymphomas.
Purpose of the Study:
- To investigate the efficacy of transcription-targeting drugs, specifically cyclin-dependent kinase 12 (CDK12) inhibitor THZ531, against DLBCL and MCL.
- To identify mechanisms of resistance to THZ531 and explore strategies to overcome it.
Main Methods:
- Pharmacogenomics and cell-based drug screening were employed to assess THZ531's effects.
- Mechanisms of resistance, including pathway activation and protein upregulation, were investigated.
- The potential of EZH2 inhibitors to reverse THZ531 resistance was evaluated.
Main Results:
- THZ531 demonstrated potent inhibition of oncogenic transcriptional programs, including DNA damage response and MYC targets, leading to lymphoma suppression in vitro.
- Resistance to THZ531 was associated with MEK-ERK and PI3K-AKT-mTOR pathway activation and MDR1 upregulation.
- EZH2 inhibitors reversed THZ531 resistance by inhibiting MDR1 and synergistically enhanced THZ531's anti-lymphoma effects.
Conclusions:
- CDK12 inhibitors represent a promising therapeutic strategy for DLBCL and MCL.
- Combination therapy with CDK12 and EZH2 inhibitors may offer an effective approach for treating drug-resistant DLBCL and MCL.
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