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      Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer

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          Abstract

          Pharmacological inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are now an established standard of care for patients with advanced hormone receptor-positive breast cancer. The canonical mechanism underlying CDK4/6 inhibitor activity is the suppression of phosphorylation of the retinoblastoma tumor suppressor protein, which serves to prevent cancer cell proliferation. Recent data suggest that these agents induce other diverse effects within both tumor and stromal compartments, which serve to explain aspects of their clinical activity. Here, we review these phenomena and discuss how they might be leveraged in the development of novel CDK4/6 inhibitor-containing combination treatments. We also briefly review the various known mechanisms of acquired resistance in the clinical setting.

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          Most cited references112

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            The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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                Author and article information

                Contributors
                shom.goel@petermac.org
                Journal
                Breast Cancer Res
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central (London )
                1465-5411
                1465-542X
                5 March 2022
                5 March 2022
                2022
                : 24
                : 17
                Affiliations
                [1 ]GRID grid.1055.1, ISNI 0000000403978434, Peter MacCallum Cancer Centre, ; 305 Grattan St, Melbourne, VIC 3000 Australia
                [2 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Sir Peter MacCallum Department of Oncology, , University of Melbourne, ; Parkville, VIC 3052 Australia
                Author information
                http://orcid.org/0000-0001-8329-9084
                Article
                1510
                10.1186/s13058-022-01510-6
                8898415
                35248122
                d2bd38d8-db0a-46eb-bd7e-4745708cee8e
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 11 August 2021
                : 20 February 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100009634, susan g. komen;
                Award ID: CCR18547966
                Award Recipient :
                Funded by: national health and medical research council
                Award ID: GNT1177357
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, national cancer institute;
                Award ID: P50 CA168504
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                Oncology & Radiotherapy
                cyclin-dependent kinase,cdk4/6,cell cycle,breast cancer,combination therapy,drug resistance

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