Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
Department of Bioinformatics and Computer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
Blood Cancer J. 2023 Feb 17;13(1):27. doi: 10.1038/s41408-023-00799-6.
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.
套细胞淋巴瘤（MCL）的治疗仍然面临着复发和耐药的挑战，尤其是在那些存在肿瘤抑制因子 ATM 和 TP53 体细胞突变的患者中，这些突变随着耐药的出现和疾病的进展而积累，这与我们的 OncoPrint 结果一致，即在复发/难治性（R/R）MCL 中，ATM 和 TP53 的改变最为常见。我们证明了在 R/R MCL 中，蛋白精氨酸甲基转移酶 5（PRMT5）上调，这预示着预后不良。PRMT5 抑制剂在 ATM 和/或 TP53 突变的 MCL 小鼠模型中或对 CD19 靶向 CAR T 细胞治疗耐药的模型中显示出了显著的抗肿瘤作用。PRMT5 的基因敲除在体内也能强有力地抑制肿瘤生长。通过使用它们的抑制剂共同靶向 PRMT5、ATR 或 CDK4，在体外和体内都显示出协同的抗肿瘤作用。我们的研究结果为针对高突变负荷的 R/R MCL 提供了一种针对多个 PRMT5 协调的肿瘤促进过程的合理联合治疗策略。
