用 Venetoclax 靶向 BCL2 可增强 KRASG12D 抑制剂 MRTX1133 对胰腺癌的疗效

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-11-04 DOI:10.1158/0008-5472.CAN-23-3574
Jeffrey H Becker, Anastasia E Metropulos, Christina Spaulding, Alejandra M Marinelarena, Mario A Shields, Daniel R Principe, Thao D Pham, Hidayatullah G Munshi
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引用次数: 0

摘要

MRTX1133目前正在对携带KRASG12D突变的胰腺导管腺癌(PDAC)患者进行评估。联合策略有可能增强 MRTX1133 的疗效,进一步促进细胞死亡和肿瘤消退。在这项研究中,我们证明了MRTX1133能提高PDAC细胞中促凋亡蛋白BIM的水平,并使细胞对FDA批准的BCL2抑制剂venetoclax敏感。MRTX1133和venetoclax联合治疗可导致细胞死亡,并抑制三维培养物的生长。联合治疗诱导的细胞凋亡需要 BIM。同样,MRTX1133治疗的肿瘤也诱导了BIM,而Venetoclax增强了MRTX1133在体内的疗效。在三维培养中,Venetoclax还能使MRTX1133耐药的PDAC细胞对MRTX1133重新敏感,耐药细胞形成的肿瘤对MRTX1133和venetoclax的联合治疗有反应。这些结果为MRTX1133和venetoclax在PDAC患者中的临床试验提供了依据。
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Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.

MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in patients with PDAC. Significance: The combination of MRTX1133 and the FDA-approved drug venetoclax promotes cancer cell death and tumor regression in pancreatic ductal adenocarcinoma, providing rationale for testing venetoclax with KRASG12D inhibitors in patients with pancreatic cancer.

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来源期刊
Cancer research
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.
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