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

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

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

Cancer Discov. 2024 Dec 2;14(12):2430-2449. doi: 10.1158/2159-8290.CD-23-0866.

Authors

Patrick Loi^#^{1

2}, Amy E Schade^#^{1

2}, Carrie L Rodriguez^{1

2}, Anjana Krishnan^{1

2}, Naiara Perurena^{1

2}, Van T M Nguyen³, Yilin Xu^{4

5

6

7}, Marina Watanabe^{1

2}, Rachel A Davis^{1

2}, Alycia Gardner^{1

2}, Natalie F Pilla^{1

2}, Kaia Mattioli^{1

2}, Olesja Popow^{2

8}, Nuray Gunduz^{9

10}, Tamsin R M Lannagan^{9

10}, Samantha Fitzgerald^{2

8

11}, Ewa T Sicinska⁸, Jia-Ren Lin^{4

5

6

7}, William Tan⁸, Lauren K Brais⁸, Kevin M Haigis^{2

8}, Marios Giannakis^{2

8

11}, Kimmie Ng⁸, Sandro Santagata^{4

5

6

7}, Kristian Helin³, Owen J Sansom^{9

10}, Karen Cichowski^{1

2

4}

Affiliations

¹ Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
² Harvard Medical School, Boston, Massachusetts.
³ Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom.
⁴ Ludwig Center at Harvard, Boston, Massachusetts.
⁵ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts.
⁶ Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.
⁷ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
⁸ Dana Farber Institute, Boston, Massachusetts.
⁹ CRUK Beatson Institute, Glasgow, United Kingdom.
¹⁰ School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
¹¹ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

^# Contributed equally.

Abstract

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.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Cell Differentiation* / drug effects
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / pathology
Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein / genetics
Epigenesis, Genetic*
Humans
Mice
Mutation*
Proto-Oncogene Proteins p21(ras)* / genetics
Wnt Signaling Pathway / drug effects

Substances

Proto-Oncogene Proteins p21(ras)
KRAS protein, human
Enhancer of Zeste Homolog 2 Protein
EZH2 protein, human
Antineoplastic Agents

Abstract

MeSH terms

Substances

Grants and funding