2. Academic Validation
  3. MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer

MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer

  • J Exp Med. 2023 Nov 6;220(11):e20211743. doi: 10.1084/jem.20211743.
Jinhyuk Bhin # 1 2 3 4,  Julia Yemelyanenko # 2 3,  Xue Chao 2 3,  Sjoerd Klarenbeek 5,  Mark Opdam 2,  Yuval Malka 3 6,  Liesbeth Hoekman 7,  Dinja Kruger 2 8,  Onno Bleijerveld 7,  Chiara S Brambillasca 2 3,  Justin Sprengers 9,  Bjørn Siteur 9,  Stefano Annunziato 2 3,  Matthijs J van Haren 10,  Nathaniel I Martin 10,  Marieke van de Ven 9,  Dennis Peters 11,  Reuven Agami 3 6,  Sabine C Linn 2 12,  Epie Boven 8,  Maarten Altelaar 7 13 14,  Jos Jonkers 2 3,  Daniel Zingg 2 3,  Lodewyk F A Wessels 1 3
Affiliations

Affiliations

  • 1 Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 2 Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 3 Oncode Institute , Utrecht, Netherlands.
  • 4 Department of Biomedical System Informatics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 5 Experimental Animal Pathology, Netherlands Cancer Institute , Amsterdam, Netherlands.
  • 6 Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 7 Proteomics Facility, Netherlands Cancer Institute , Amsterdam, Netherlands.
  • 8 Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam/Cancer Center Amsterdam, Amsterdam, Netherlands.
  • 9 Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute , Amsterdam, Netherlands.
  • 10 Biological Chemistry Group, Institute of Biology Leiden, Leiden University , Leiden, Netherlands.
  • 11 Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute , Amsterdam, Netherlands.
  • 12 Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 13 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Utrecht, Netherlands.
  • 14 Netherlands Proteomics Centre, Utrecht, Netherlands.
  • # Contributed equally.
PMID: 37642941 DOI: 10.1084/jem.20211743
Abstract

Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast Cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast Cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast Cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast Cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast Cancer patients for mTOR-targeted therapies.

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