2. Academic Validation
  3. Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations

Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations

  • Blood Cancer J. 2023 Feb 17;13(1):27. doi: 10.1038/s41408-023-00799-6.
Yuxuan Che # 1,  Yang Liu # 1,  Yixin Yao 2,  Holly A Hill 3,  Yijing Li 1,  Qingsong Cai 1,  Fangfang Yan 4,  Preetesh Jain 1,  Wei Wang 1,  Lixin Rui 5,  Michael Wang 6 7
Affiliations

Affiliations

  • 1 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
  • 2 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 3 Department of Bioinformatics and Computer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
  • 4 School of Biomedical Informatics, University of Texas Health Science Center at Houston, 7000 Fannin Street, Houston, TX, 77030, USA.
  • 5 Department of Medicine, the University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI, 53726, USA.
  • 6 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 7 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
  • # Contributed equally.
PMID: 36797243 DOI: 10.1038/s41408-023-00799-6
Abstract

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. Genetic knockout of PRMT5 robustly inhibited tumor growth in vivo. Co-targeting PRMT5, and ATR or CDK4 by using their inhibitors showed synergistic antitumor effects both in vitro and in vivo. Our results have provided a rational combination therapeutic strategy targeting multiple PRMT5-coordinated tumor-promoting processes for the treatment of R/R MCL with high mutation burdens.

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