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
{"title":"Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers.","authors":"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","doi":"10.1158/2159-8290.CD-23-0866","DOIUrl":null,"url":null,"abstract":"<p><p>Current treatments for KRAS-mutant colorectal cancers (CRCs) are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of the histone methyltransferase, EZH2, synergize with various RAS pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress WNT-driven transcription and drive CRCs into a more differentiated cell state by inducing the Groucho/TLE corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the pro-apoptotic protein BMF, which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant CRCs and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7000,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.CD-23-0866","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Current treatments for KRAS-mutant colorectal cancers (CRCs) are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of the histone methyltransferase, EZH2, synergize with various RAS pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress WNT-driven transcription and drive CRCs into a more differentiated cell state by inducing the Groucho/TLE corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the pro-apoptotic protein BMF, which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant CRCs and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.
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.