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.
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 / Occhipinti, G.; Romagnoli, E.; Santoni, M.; Cimadamore, A.; Sorgentoni, G.; Cecati, M.; Giulietti, M.; Battelli, N.; Maccioni, A.; Storti, N.; Cheng, L.; Principato, G.; Montironi, R.; Piva, F.. - In: FRONTIERS IN GENETICS. - ISSN 1664-8021. - 11:(2020), p. 349. [10.3389/fgene.2020.00349]