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Mol Cancer Ther2025;24(10):1511-1526.October 1, 2025Journal Article

Depleting the Action of EZH2 through PI3K-mTOR Inhibition to Overcome Metastasis and Immunotherapy Resistance in Triple-Negative Breast Cancer.

Michelle Melino1, Wen Juan Tu1, Helle Bielefeldt-Ohmann2,3, Martina Proctor1, Taniya Ahuja1, John Vandermeide1, Amanda L Bain1, Gahyathiri Nallan1, Sal Lee Goh1, Thiru Prasanna4,5, Jane E Dahlstrom6,7, Mariska Miranda1, Ramesh Kumar Chaudhary8, Aravind Anandam8, Sumit Chaudhary8, Jonathan T Seal9, Debottam Sinha10, Shaoqian Zhang11, Tam Hong Nguyen12, Sriganesh Srihari13, Gunter Hartel14,15, Amy Ives16, Laeeq Malik4, Desmond Yip4,6, Michelle Nottage16, Melissa Eastgate16,17, Sudha Rao1
1Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
2School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
3Australian Infectious Diseases Research Centre, Brisbane, Australia.
4Department of Medical Oncology, The Canberra Hospital, Garran, Australia.
5Australian National University, Canberra, Australia.
6School of Medicine and Psychology, Australian National University, Canberra, Australia.
7ACT Pathology, The Canberra Hospital, Canberra Health Services, Garran, Australia.
8Department of In Vivo Pharmacology, Biology, Sai Life Sciences, Hyderabad, India.
9Medicinal Chemistry, Sai Life Sciences Ltd, Macclesfield, United Kingdom.
10Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, Australia.
11Akoya Biosciences, Marlborough, Massachusetts.
12Flow cytometry and Imaging Facility, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
13Tumour Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
14Statistics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
15Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Australia.
16Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Australia.
17Faculty of Medicine, University of Queensland, Brisbane, Australia.
PubMed PMC DOI PDF

Abstract

Almost half of patients with triple-negative breast cancer develop distant metastases, heralding unfavorable outcomes. Here, we provide novel insights into the contribution of the PI3K-mTOR pathway to the triple-negative breast cancer phenotypes that promote growth, migration, metastasis, and therapy resistance. Specifically, we demonstrate that dual targeting of PI3K and mTOR but not PI3K alone i…

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