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
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 comp...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2020.00349/full |
| _version_ | 1819043965095116800 |
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| author | Giulia Occhipinti Emanuela Romagnoli Matteo Santoni Alessia Cimadamore Giulia Sorgentoni Monia Cecati Matteo Giulietti Nicola Battelli Alessandro Maccioni Nadia Storti Liang Cheng Giovanni Principato Rodolfo Montironi Francesco Piva |
| author_facet | Giulia Occhipinti Emanuela Romagnoli Matteo Santoni Alessia Cimadamore Giulia Sorgentoni Monia Cecati Matteo Giulietti Nicola Battelli Alessandro Maccioni Nadia Storti Liang Cheng Giovanni Principato Rodolfo Montironi Francesco Piva |
| author_sort | Giulia Occhipinti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T10:05:09Z |
| format | Article |
| id | doaj.art-b44af9987ced4980a6b469e387bbac78 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-21T10:05:09Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-b44af9987ced4980a6b469e387bbac782022-12-21T19:07:51ZengFrontiers Media S.A.Frontiers in Genetics1664-80212020-04-011110.3389/fgene.2020.00349501025Sequential or Concomitant Inhibition of Cyclin-Dependent Kinase 4/6 Before mTOR Pathway in Hormone-Positive HER2 Negative Breast Cancer: Biological Insights and Clinical ImplicationsGiulia Occhipinti0Emanuela Romagnoli1Matteo Santoni2Alessia Cimadamore3Giulia Sorgentoni4Monia Cecati5Matteo Giulietti6Nicola Battelli7Alessandro Maccioni8Nadia Storti9Liang Cheng10Giovanni Principato11Rodolfo Montironi12Francesco Piva13Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, ItalyOncology Unit, Macerata Hospital, Macerata, ItalyOncology Unit, Macerata Hospital, Macerata, ItalySection of Pathological Anatomy, School of Medicine, United Hospitals, Polytechnic University of the Marche Region, Ancona, ItalyOncology Unit, Macerata Hospital, Macerata, ItalyDepartment of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, ItalyDepartment of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, ItalyOncology Unit, Macerata Hospital, Macerata, ItalyDirezione Area Vasta 3, Macerata, ItalyDirezione Sanitaria Azienda Sanitaria Unica Regionale, Ancona, ItalyDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, ItalySection of Pathological Anatomy, School of Medicine, United Hospitals, Polytechnic University of the Marche Region, Ancona, ItalyDepartment of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, ItalyAbout 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.https://www.frontiersin.org/article/10.3389/fgene.2020.00349/fullbreast cancerestrogen receptorcyclin-dependent kinases (CDKs)CDK inhibitorsmechanisms of resistance |
| spellingShingle | Giulia Occhipinti Emanuela Romagnoli Matteo Santoni Alessia Cimadamore Giulia Sorgentoni Monia Cecati Matteo Giulietti Nicola Battelli Alessandro Maccioni Nadia Storti Liang Cheng Giovanni Principato Rodolfo Montironi Francesco Piva 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 breast cancer estrogen receptor cyclin-dependent kinases (CDKs) CDK inhibitors mechanisms of resistance |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | breast cancer estrogen receptor cyclin-dependent kinases (CDKs) CDK inhibitors mechanisms of resistance |
| url | https://www.frontiersin.org/article/10.3389/fgene.2020.00349/full |
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