Abstract
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.
Highlights
Breast cancer presents a significant health burden worldwide according to the International Agency for Research on Cancer1
The blockade of CDK4/6 activity by therapeutic inhibitors leads to retinoblastoma protein (Rb) de-phosphorylation and to the subsequent strengthening of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway that plays a pivotal role in the control of cell growth, migration and metabolism (Cretella et al, 2018; Figure 2). mTORC2 inhibition lowers cell proliferation by weakening of mTORC1, cyclin D, Rb axis
The identification of patients who develop resistance to CDK4/6 inhibitors due to the activation of PI3K/AKT/mTOR pathway will pave the way to the combination of abemaciclib, ribociclib or palbociclib with everolimus, alpelisib or copanlisib into daily clinical practice
Summary
About 75% of all breast cancers are hormone receptor-positive (HR+). 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. The little evidence dealing with this topic suggests that pretreatment 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
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