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Non-Hodgkin Lymphoma
Response and resistance to CDK12 inhibition in aggressive B-cell lymphomas
Jing Gao,1,* Michelle Y. Wang,1,* Yuan Ren,1 Tint Lwin,1 Tao Li,1 Joy C. Yan,1 Eduardo M. Sotomayor,2 Derek R. Duckett,1 Bijal D. Shah,3 Kenneth H. Shain,3 Xiaohong Zhao1 and Jianguo Tao4
1Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 2Cancer Institute, Tampa General Hospital,Tampa, FL; 3Departments of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL and 4(Previous affiliation) Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
*JG and MYW contributed equally as co-first authors.
ABSTRACT
Despite significant progress in the treatment of patients with dif- fuse 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 transcrip- tional 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.
Introduction
MYC is a transcription factor that promotes oncogenesis by activating and repress- ing its target genes that control cell growth and proliferation.1 While MYC has been described as a defining feature and the driving oncogene for Burkitt lymphoma, the significance of MYC has also been recognized in other non-Hodgkin lymphomas.2 MYC, which has been detected in 15-20% of diffuse large B-cell lymphomas (DLBCL), is associated with an adverse prognosis as a result of chemoresistance and, shortened survival. In mantle cell lymphoma (MCL), increased expression of MYC has been found to be associated with poor prognosis and more aggressive disease.3 MYC overexpression has also been implicated in high-grade large cell transformation.4 Despite current modes of intensive chemotherapy and immunother- apy, MCL and other MYC-associated lymphomas are aggressive diseases that respond poorly to chemoimmunotherapy and affected patients have a dismal sur- vival. Identification of effective strategies to target these aggressive lymphomas rep- resents an urgent need.
Recently, we integrated data from our unbiased activity-based proteomic profiling, RNA-sequencing, and chromatin immunoprecipitation (ChIP) assays with sequenc- ing studies. We found that the aggressive progression and development of drug resist- ance in MCL and MYC-associated lymphomas require complex transcriptome and kinome remodeling of cellular signaling networks, positive feedback loops that amplify pro-survival and growth signals.5 Rather than there being a single mechanism
Ferrata Storti Foundation
Haematologica 2022 Volume 107(5):1119-1130
Correspondence:
JIANGUO TAO
dtep642021@gmail.com
Received: March 10, 2021. Accepted: June 10, 2021. Pre-published: June 24, 2021.
https://doi.org/10.3324/haematol.2021.278743 ©2022 Ferrata Storti Foundation
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