Occhipinti, GiuliaRomagnoli, EmanuelaSantoni, MatteoCimadamore, AlessiaSorgentoni, GiuliaCecati, MoniaGiulietti, MatteoBattelli, NicolaMaccioni, AlessandroStorti, NadiaCheng, LiangPrincipato, GiovanniMontironi, RodolfoPiva, Francesco2020-06-242020-06-242020Occhipinti, 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. (2020). 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, 11, 349. https://doi.org/10.3389/fgene.2020.00349https://hdl.handle.net/1805/23079About 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.en-USAttribution 4.0 InternationalBreast cancerEstrogen receptorCyclin-dependent kinases (CDKs)CDK inhibitorsMechanisms of resistanceArticle