Triple negative breast cancer (TNBC) remains the most aggressive and deadly type of breast cancer, but new findings from cancer researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, are pointing the way toward therapeutic strategies that could be tested in clinical trials in the future. Using patient-derived samples in pre-clinical work, researchers discovered that by combining two therapeutic agents they could nudge TNBC cells into a more treatable state. Findings are published in Nature.
“When combined, these therapeutic agents can hijack signals that occur naturally in the body to eliminate breast cells after the cessation of lactation to kill these aggressive cancer cells,” said senior author Karen Cichowski, PhD, of the Division of Genetics at Brigham and Women’s Hospital (BWH). “Our results provide compelling support for the development of clinical trials to test whether combining these agents could benefit patients with TNBC.”
Specifically, the researchers discovered that that by combining two types of agents known as EZH2 and AKT inhibitors, they could coax TNBC cells to differentiate. Once the cells are differentiated, these agents kill tumor cells by triggering a process similar to involution, which normally occurs when breast tissue returns to a non-lactating state after a mother stops producing breast milk. The researchers also used machine learning to predict patient responses—another step that could help set the stage for clinical trials in patients.
In future studies, the researchers are interested in exploring whether similar drug combinations may be effective in other tumor types.
Authorship: In addition to Cichowski, BWH authors include Amy E Schade, Naiara Perurena, Yoona Yang, Carrie L Rodriguez, Anjana Krishnan, Alycia Gardner, Patrick Loi, Yilin Xu, Van TM Nguyen, GM Mastellone, Natalie F Pilla, Marina Watanabe, Keiichi Ota, Rachel A Davis, Kaia Mattioli, Dongxi Xiang, Zhe Li, and Sandro Santagata.
Disclosures: Cichowski is an advisor at Genentech and serves on the scientific advisory board of Erasca, Inc. Disclosures for other authors can be found in the paper.
Funding: This work was supported by a grant from the Cancer Research UK Grand Challenge and the Mark Foundation for Cancer Research to the SPECIFICANCER team (KC) and a DOD BC201085P1 Transformative Breast Cancer Consortium Award.
Paper cited: Schade AE et al. “AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution” Nature DOI: 10.1038/s41586-024-08031-6
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About Mass General Brigham
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Journal
Nature
Method of Research
Experimental study
Subject of Research
Cells
Article Title
AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution
Article Publication Date
9-Oct-2024
COI Statement
K.C. is an advisor at Genentech and serves on the scientific advisory board of Erasca, Inc. S.M.T. has consulting or advisory roles at Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, and ARC Therapeutics; and received institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate Therapeutics, Sanofi, and Seattle Genetics. PKS is a co-founder and member of the BOD of Glencoe Software, member of the BOD for Applied Biomath, member of the SAB for RareCyte, NanoString, and Montai Health, holds equity in Glencoe, Applied Biomath, and RareCyte, consults for Merck, and has received research funding to the institution from Novartis and Merck in the past five years. A.C.G.C. has grant/research funding to institution from Gilead Sciences, AstraZeneca, Daiichi-Sankyo, Merck, Zenith 435 Epigenetics, Bristol-Myers Squibb, Novartis, Foundation Medicine, and Biovica; serves as Consultant/Scientific Advisory Board for AstraZeneca, Daiichi-Sankyo, and Novartis; has received honoraria from AstraZeneca and Daiichi- Sankyo; and has other financial or materials support from Roche/Genentech, Gilead Sciences, AstraZeneca, Novartis, and Merck. K.H. is a consultant for and a co-founder of Dania Therapeutics Aps and a scientific advisor for Hannibal Health Innovation. S.R.V.K. is a founder and consultant at Faeth Therapeutics and Transomic Technologies. D.A.B. is a consultant for N of One/QIAGEN, and Tango Therapeutics; is a founder and shareholder in Xsphera Biosciences; has received honoraria from Merck, H3 Biomedicine/Esai, EMD Serono, Gilead Sciences, Abbvie, and Madalon Consulting; and has received research grants from BMS, Takeda, Novartis, Gilead, and Lilly. No other authors report competing interests.