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维奈克拉靶向 BCL2 增强 KRASG12D 抑制剂 MRTX1133 在胰腺癌中的疗效。

Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.

机构信息

Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Jesse Brown VA Medical Center, Chicago, Illinois.

出版信息

Cancer Res. 2024 Nov 4;84(21):3629-3639. doi: 10.1158/0008-5472.CAN-23-3574.

DOI:10.1158/0008-5472.CAN-23-3574
PMID:39137400
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11532783/
Abstract

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.

摘要

MRTX1133 目前正在携带 KRASG12D 突变的胰腺导管腺癌 (PDAC) 肿瘤患者中进行评估。联合策略有可能增强 MRTX1133 的疗效，以进一步促进细胞死亡和肿瘤消退。在这项研究中，我们证明 MRTX1133 增加了 PDAC 细胞中促凋亡蛋白 BIM 的水平，并使 FDA 批准的 BCL2 抑制剂 venetoclax 敏感。MRTX1133 和 venetoclax 的联合治疗导致 3D 培养物中的细胞死亡和生长抑制。BIM 是联合治疗诱导的细胞凋亡所必需的。一致地，在接受 MRTX1133 治疗的肿瘤中诱导了 BIM，并且 venetoclax 增强了 MRTX1133 在体内的疗效。venetoclax 还可以使 MRTX1133 耐药的 PDAC 细胞在 3D 培养物中对 MRTX1133 重新敏感，并且来自耐药细胞的肿瘤对 MRTX1133 和 venetoclax 的联合治疗有反应。这些结果为在 PDAC 患者中测试 MRTX1133 和 venetoclax 的临床测试提供了依据。意义：MRTX1133 和 FDA 批准的药物 venetoclax 的联合促进了胰腺导管腺癌中的癌细胞死亡和肿瘤消退，为在胰腺癌患者中用 KRASG12D 抑制剂测试 venetoclax 提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5dd/11532783/43f8ae2ed3d5/can-23-3574_f5.jpg
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本文引用的文献

1
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Nat Med. 2024 Apr;30(4):969-983. doi: 10.1038/s41591-024-02903-0. Epub 2024 Apr 18.
2
Combinatorial strategies to target RAS-driven cancers.靶向 RAS 驱动型癌症的组合策略。
Nat Rev Cancer. 2024 May;24(5):316-337. doi: 10.1038/s41568-024-00679-6. Epub 2024 Apr 16.
3
Targeting KRAS in Non-Small-Cell Lung Cancer: Current Standards and Developments.针对非小细胞肺癌中的 KRAS：当前标准和进展。
Drugs. 2024 May;84(5):527-548. doi: 10.1007/s40265-024-02030-7. Epub 2024 Apr 16.
4
Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.阿达格拉西布联合西妥昔单抗治疗 KRASG12C 突变型转移性结直肠癌患者的疗效和安全性。
Cancer Discov. 2024 Jun 3;14(6):982-993. doi: 10.1158/2159-8290.CD-24-0217.
5
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Cancer Res. 2024 Apr 1;84(7):1115-1132. doi: 10.1158/0008-5472.CAN-23-2504.
6
Cancer statistics, 2024.2024年癌症统计数据。
CA Cancer J Clin. 2024 Jan-Feb;74(1):12-49. doi: 10.3322/caac.21820. Epub 2024 Jan 17.
7
A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer.小分子，大作为：MRTX1133 靶向胰腺癌中的 KRASG12D 突变。
Clin Cancer Res. 2024 Feb 16;30(4):655-662. doi: 10.1158/1078-0432.CCR-23-2098.
8
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Cancer Cell. 2023 Sep 11;41(9):1606-1620.e8. doi: 10.1016/j.ccell.2023.07.002. Epub 2023 Aug 24.
9
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J Clin Oncol. 2023 Sep 1;41(25):4097-4106. doi: 10.1200/JCO.23.00434. Epub 2023 Apr 26.
10
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Front Oncol. 2023 Feb 21;13:1130034. doi: 10.3389/fonc.2023.1130034. eCollection 2023.