Sequential or Concomitant Inhibition of Cyclin-Dependent Kinase 4/6 Before mTOR Pathway in Hormone-Positive HER2 Negative Breast Cancer: Biological Insights and Clinical Implications

Frontiers in Genetics

Liang Cheng¹  Francesco Piva²  Giovanni Principato²  Matteo Giulietti²  Monia Cecati²  Giulia Occhipinti²  Alessandro Maccioni³  Nadia Storti⁴  Matteo Santoni⁵  Nicola Battelli⁵  Emanuela Romagnoli⁵  Giulia Sorgentoni⁵  Rodolfo Montironi⁶  Alessia Cimadamore⁶ 

[1] Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States;Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, Italy;Direzione Area Vasta 3, Macerata, Italy;Direzione Sanitaria Azienda Sanitaria Unica Regionale, Ancona, Italy;Oncology Unit, Macerata Hospital, Macerata, Italy;Section of Pathological Anatomy, School of Medicine, United Hospitals, Polytechnic University of the Marche Region, Ancona, Italy;

关键词: breast cancer;    estrogen receptor;    cyclin-dependent kinases (CDKs);    CDK inhibitors;    mechanisms of resistance;   

DOI  :  10.3389/fgene.2020.00349

来源: DOAJ

【 摘 要 】

About 75% of all breast cancers are hormone receptor-positive (HR+). However, the efficacy of endocrine therapy is limited due to the high rate of either pre-existing or acquired resistance. In this work we reconstructed the pathways around estrogen receptor (ER), mTOR, and cyclin D in order to compare the effects of CDK4/6 and PI3K/AKT/mTOR inhibitors. A positive feedback loop links mTOR and ER that support each other. We subsequently considered whether a combined or sequential inhibition of CDK4/6 and PI3K/AKT/mTOR could ensure better results. Studies indicate that inhibition of CDK4/6 activates mTOR as an escape mechanism to ensure cell proliferation. In literature, the little evidence dealing with this topic suggests that pre-treatment with mTOR pathway inhibitors could prevent or delay the onset of CDK4/6 inhibitor resistance. Additional studies are needed in order to find biomarkers that can identify patients who will develop this resistance and in whom the sensitivity to CDK4/6 inhibitors can be restored.

【 授权许可】

Unknown