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

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 n...

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Published in:NPJ precision oncology 2022-09, Vol.6 (1), p.68-68, Article 68
Main Authors: Al-Qasem, Abeer J., Alves, Carla L., Ehmsen, Sidse, Tuttolomondo, Martina, Terp, Mikkel G., Johansen, Lene E., Vever, Henriette, Hoeg, Luna V. A., Elias, Daniel, Bak, Martin, Ditzel, Henrik J.
Format: Article
Language:English
Subjects:
631/67/1059/602
692/53/2423
Biomarkers
Breast cancer
Cancer Research
Cell cycle
Drug resistance
Gene Therapy
Human Genetics
Internal Medicine
Medicine
Medicine & Public Health
Oncology
Targeted cancer therapy
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Summary: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.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-022-00311-6