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Author Spotlight: Advancing the Detection of Low-Frequency Mutations in Cancer Tissues
Published on: August 23, 2024
Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53
Yuxuan Che1, Yang Liu1, Yixin Yao2
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
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.
Insights
Protein arginine methyltransferase-5 (PRMT5) shows promise for treating relapsed mantle cell lymphoma (MCL). Inhibiting PRMT5, especially in patients with ATM/TP53 mutations, demonstrated significant antitumor effects in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mantle cell lymphoma (MCL) presents challenges due to relapses and therapy resistance.
- Somatic mutations in ATM and TP53 are associated with disease progression and resistance in MCL.
- Relapsed/refractory (R/R) MCL, particularly with ATM/TP53 alterations, requires novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of protein arginine methyltransferase-5 (PRMT5) in R/R MCL.
- To evaluate the therapeutic potential of PRMT5 inhibitors in preclinical MCL models.
- To identify combination strategies for enhanced efficacy in R/R MCL.
Main Methods:
- Analysis of PRMT5 expression in R/R MCL patient samples.
- Assessment of PRMT5 inhibitors in mouse models of MCL with ATM/TP53 mutations or CAR T-cell therapy resistance.
- In vitro and in vivo evaluation of PRMT5 genetic knockout.
- Combination studies with ATR or CDK4 inhibitors.
Main Results:
- PRMT5 was found to be upregulated in R/R MCL, correlating with a poor prognosis.
- PRMT5 inhibitors demonstrated significant antitumor activity in preclinical MCL models.
- Genetic ablation of PRMT5 effectively suppressed tumor growth in vivo.
- Co-targeting PRMT5 with ATR or CDK4 inhibitors yielded synergistic antitumor effects.
Conclusions:
- PRMT5 is a promising therapeutic target for R/R MCL.
- PRMT5 inhibition offers a potential treatment avenue for MCL patients with ATM/TP53 mutations or refractory disease.
- Combination therapies targeting PRMT5 with ATR or CDK4 inhibitors represent a rational strategy for R/R MCL with high mutation burdens.
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