Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors is an Effective Treatment Strategy for MTAP-Deleted KRAS-Mutant Pancreatic Cancer.

IF 16.6 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2025-07-22 DOI:10.1158/0008-5472.can-25-1507

Kristina Drizyte-Miller,Lars D Engstrom,Jeffrey A Klomp,Clint A Stalnecker,Addison G Stamey,Khalilah E Taylor,Mallory K Roach,Ryan Robb,Laura M Waters,Andrew Calinisan,Seamus Degan,Wen-Hsuan Chang,Xousaen M Helu,David Nguyen,Elisa Baldelli,Mariaelena Pierobon,Emanuel F Petricoin,David M Briere,Jill Hallin,James G Christensen,Kirsten L Bryant,Adrienne D Cox,Peter Olson,Channing J Der

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引用次数: 0

Abstract

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in MTAP-deleted (MTAP-del) cancers. The MTA-cooperative PRMT5 inhibitor BMS-986504 exhibited potent and selective anti-tumor activity in MTAP-del preclinical models and demonstrated activity in MTAP-del patients without the toxicity associated with previous PRMT5 inhibitors. Here, we focused on pancreatic ductal adenocarcinoma (PDAC), ~22% of which are MTAP-del, and demonstrated that BMS-986504 suppressed PRMT5 function and cell growth in MTAP-del cells and xenograft models. CRISPR/Cas9 loss-of-function screens implicated co-targeting KRAS as a combination strategy. Concurrent inhibition of PRMT5 and KRASG12C/D enhanced and prolonged suppression of PDAC growth. RNA-sequencing analysis revealed that PRMT5 inhibition disrupted RNA splicing of genes essential for PDAC growth. While PRMT5 and KRAS regulated distinct transcriptomes, they converged on pathways governing cancer cell growth and expression of PDAC-essential genes. These findings provide rationale for combined inhibition of PRMT5 and KRAS in MTAP-deleted/KRAS-mutant PDAC.

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mta -协同PRMT5抑制剂BMS-986504与KRAS抑制剂联合治疗mtap缺失KRAS突变型胰腺癌的有效治疗策略

蛋白精氨酸甲基转移酶5 （PRMT5）是mtap缺失（MTAP-del）癌症的合成致死靶点。与mta合作的PRMT5抑制剂BMS-986504在MTAP-del临床前模型中显示出有效和选择性的抗肿瘤活性，并且在MTAP-del患者中显示出活性，而没有与先前的PRMT5抑制剂相关的毒性。在此，我们重点研究了约22%的MTAP-del型胰腺导管腺癌（PDAC），并在MTAP-del细胞和异种移植模型中证明了BMS-986504抑制PRMT5功能和细胞生长。CRISPR/Cas9功能缺失筛选涉及联合靶向KRAS。同时抑制PRMT5和KRASG12C/D增强并延长了PDAC生长的抑制。RNA测序分析显示，PRMT5抑制破坏了PDAC生长所需基因的RNA剪接。虽然PRMT5和KRAS调节不同的转录组，但它们在控制癌细胞生长和pdac必需基因表达的途径上趋同。这些发现为mtap缺失/KRAS突变PDAC中PRMT5和KRAS的联合抑制提供了理论依据。

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来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.