2. Academic Validation
  3. Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers

Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers

  • Cancer Discov. 2024 Aug 12. doi: 10.1158/2159-8290.CD-23-0866.
Patrick Loi 1,  Amy E Schade 2,  Carrie L Rodriguez 1,  Anjana Krishnan 1,  Naiara Perurena 1,  Van T M Nguyen 3,  Yilin Xu 4,  Marina Watanabe 1,  Rachel A Davis 1,  Alycia Gardner 2,  Natalie F Pilla 1,  Kaia Mattioli 1,  Olesja Popow 5,  Nuray Gunduz 6,  Tamsin R M Lannagan 7,  Samantha Fitzgerald 8,  Ewa T Sicinska 8,  Jia-Ren Lin 9,  William Tan 8,  Lauren K Brais 8,  Kevin M Haigis 8,  Marios Giannakis 8,  Kimmie Ng 8,  Sandro Santagata 10,  Kristian Helin 11,  Owen J Sansom 12,  Karen Cichowski 9
Affiliations

Affiliations

  • 1 Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
  • 2 Brigham and Women's Hospital, Boston, MA, United States.
  • 3 Imperial Centre for Translational and Experimental Medecine, London, United Kingdom.
  • 4 Harvard University, United States.
  • 5 Dana-Farber Cancer Institute, United States.
  • 6 Cancer Research UK Beatson Institute, Glasgow, Scotland, United Kingdom.
  • 7 Beatson Institute for Cancer Research, Glasgow, South Australia, United Kingdom.
  • 8 Dana-Farber Cancer Institute, Boston, MA, United States.
  • 9 Harvard University, Boston, MA, United States.
  • 10 Brigham and Women's Hospital, United States.
  • 11 Institute of Cancer Research, London, United Kingdom.
  • 12 CRUK Beatson Institute, Glasgow, United Kingdom.
PMID: 39121480 DOI: 10.1158/2159-8290.CD-23-0866
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.

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