表观遗传抑制剂和致癌抑制剂共同推动分化，杀死 KRAS 突变的结直肠癌。

IF 29.7 1区医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2024-12-02 DOI:10.1158/2159-8290.CD-23-0866

Patrick Loi, Amy E Schade, Carrie L Rodriguez, Anjana Krishnan, Naiara Perurena, Van T M Nguyen, Yilin Xu, Marina Watanabe, Rachel A Davis, Alycia Gardner, Natalie F Pilla, Kaia Mattioli, Olesja Popow, Nuray Gunduz, Tamsin R M Lannagan, Samantha Fitzgerald, Ewa T Sicinska, Jia-Ren Lin, William Tan, Lauren K Brais, Kevin M Haigis, Marios Giannakis, Kimmie Ng, Sandro Santagata, Kristian Helin, Owen J Sansom, Karen Cichowski

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引用次数: 0

摘要

目前对 KRAS 突变结直肠癌（CRC）的治疗常常受到细胞可塑性和重接线反应的限制。在这里，我们描述了一种同时针对表观遗传和致癌信号的有前途的治疗策略。具体来说，我们发现组蛋白甲基转移酶 EZH2 抑制剂能与各种 RAS 通路抑制剂协同作用，促进体内肿瘤的显著消退。这些药物通过诱导 Groucho/TLE 核心抑制剂 TLE4 以及 WNT 通路抑制剂和肠道分化蛋白网络，共同抑制 WNT 驱动的转录，促使 CRC 进入更分化的细胞状态。不过，这些药物也会诱导促凋亡蛋白 BMF，从而杀死这些分化程度较高的细胞。因此，可以通过激活β-catenin、阻止分化或消除BMF的表达来防止细胞死亡。总之，这些研究揭示了一种治疗 KRAS 突变性 CRC 的新方法，并说明了 EZH2 和 RAS 在致癌 WNT 信号、肠道分化和细胞凋亡方面的关键作用。

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Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers.

Significance: Combined EZH2 and RAS pathway inhibitors kill KRAS-mutant colorectal cancer cells and promote durable tumor regression in vivo. These agents function by cooperatively suppressing the WNT pathway, driving differentiation, and epigenetically reprogramming cells to permit the induction of apoptotic signals, which then kill these more differentiated tumor cells.

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.