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Front. Oncol. | doi: 10.3389/fonc.2019.00666

Mechanisms of resistance to CDK4/6 inhibitors: potential implications and biomarkers for clinical practice

 Amelia McCartney1, Ilenia Migliaccio2, Martina Bonechi2, Chiara Biagioni3, Dario Romagnoli3, Francesca De Luca2, Francesca Galardi2, Emanuela Risi1, Irene De Santo1, Matteo Benelli3, Luca Malorni1, 2 and Angelo Di Leo1*
  • 1Hospital of Prato, Italy
  • 2Sandro Pitigliani Translational Research Unit, New hospital in Prato, Italy
  • 3New Hospital of Prato (NOP), Italy

The recent arrival of CDK4/6 inhibitor agents, with an approximate doubling of progression-free survival associated with their use in hormone receptor-positive, HER2-negative advanced breast cancer, has radically changed the approach to managing this disease. However, resistance to CDK4/6 inhibitors is considered a near-inevitability in most patients. Mechanisms of resistance to these agents are multifactorial, and research in this field is still evolving. Biomarkers with the ability to identify early resistance, or to predict the likelihood of successful treatment using CDK4/6 inhibitors are yet to be identified, and represent an area of unmet clinical need. Here we present selected mechanisms of resistance to CDK4/6 inhibitors, largely focussing on roles of Rb, cyclin E1 and the PIK3CA pathway, with discussion of associated biomarkers which have been investigated and applied in recent pre-clinical and clinical studies. These biological drivers may furthermore influence clinical treatment strategies adopted beyond CDK4/6 resistance.

Keywords: CDK4/6 inhibitors, biomarker, Thymidine kinase 1 (TK1), PIK3CA, palbocicib, Ribociclib, Abemaciclib, Resistance

Received: 10 May 2019; Accepted: 08 Jul 2019.

Edited by:

Mothaffar Rimawi, Baylor College of Medicine, United States

Reviewed by:

Tomás Pascual Martinez, Department of Medical Oncology, Hospital Clínic of Barcelona, Spain
Nuria Chic, Hospital Clínic de Barcelona, Spain  

Copyright: © 2019 McCartney, Migliaccio, Bonechi, Biagioni, Romagnoli, De Luca, Galardi, Risi, De Santo, Benelli, Malorni and Di Leo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Angelo Di Leo, Hospital of Prato, Prato, Italy, angelo.dileo@uslcentro.toscana.it