Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer

  • NPJ Precis Oncol. 2022 Sep 24;6(1):68. doi: 10.1038/s41698-022-00311-6.
Abeer J Al-Qasem   #  1 ,  Carla L Alves   #  2 ,  Sidse Ehmsen  3 ,  Martina Tuttolomondo  4 ,  Mikkel G Terp  4 ,  Lene E Johansen  4 ,  Henriette Vever  4 ,  Luna V A Hoeg  4 ,  Daniel Elias  4 ,  Martin Bak  5 ,  Henrik J Ditzel  6  7  8
Affiliations
  • 1. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. [email protected].
  • 2. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. [email protected].
  • 3. Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
  • 4. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • 5. Department of Pathology, Sydvestjysk Sygehus, Esbjerg, Denmark.
  • 6. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. [email protected].
  • 7. Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark. [email protected].
  • 8. Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense, Denmark. [email protected].
  • # Contributed equally.
PMID: 36153348 DOI: 10.1038/s41698-022-00311-6
Abstract

Resistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast Cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast Cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and Apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast Cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.

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