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      Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

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          Abstract

          Deregulation of the cyclin D‐CDK4/6‐INK4‐RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle‐specific mechanisms and cell cycle‐nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.

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          Most cited references86

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          Incidence and Mortality and Epidemiology of Breast Cancer in the World.

          Breast cancer is the most common malignancy in women around the world. Information on the incidence and mortality of breast cancer is essential for planning health measures. This study aimed to investigate the incidence and mortality of breast cancer in the world using age-specific incidence and mortality rates for the year 2012 acquired from the global cancer project (GLOBOCAN 2012) as well as data about incidence and mortality of the cancer based on national reports. It was estimated that 1,671,149 new cases of breast cancer were identified and 521,907 cases of deaths due to breast cancer occurred in the world in 2012. According to GLOBOCAN, it is the most common cancer in women, accounting for 25.1% of all cancers. Breast cancer incidence in developed countries is higher, while relative mortality is greatest in less developed countries. Education of women is suggested in all countries for early detection and treatment. Plans for the control and prevention of this cancer must be a high priority for health policy makers; also, it is necessary to increase awareness of risk factors and early detection in less developed countries.
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            Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer

            Epithelial–mesenchymal transition (EMT) is known to play an important role in cancer progression, metastasis and drug resistance. Although there are controversies surrounding the causal relationship between EMT and cancer metastasis, the role of EMT in cancer drug resistance has been increasingly recognized. Numerous EMT-related signaling pathways are involved in drug resistance in cancer cells. Cells undergoing EMT show a feature similar to cancer stem cells (CSCs), such as an increase in drug efflux pumps and anti-apoptotic effects. Therefore, targeting EMT has been considered a novel opportunity to overcome cancer drug resistance. This review describes the mechanism by which EMT contributes to drug resistance in cancer cells and summarizes new advances in research in EMT-associated drug resistance.
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              CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation

              Immune checkpoint blockade, exemplified by antibodies targeting the programmed death-1 (PD-1) receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T cell activation, contributing to anti-tumor effects in vivo , due in part to de-repression of Nuclear Factor of Activated T cell (NFAT) family proteins and their target genes, critical regulators of T cell function. Although CDK4/6 inhibitors decrease T cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.
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                Author and article information

                Contributors
                ymoon@cha.ac.kr
                Journal
                Int J Cancer
                Int. J. Cancer
                10.1002/(ISSN)1097-0215
                IJC
                International Journal of Cancer
                John Wiley & Sons, Inc. (Hoboken, USA )
                0020-7136
                1097-0215
                07 January 2019
                01 September 2019
                : 145
                : 5 ( doiID: 10.1002/ijc.v145.5 )
                : 1179-1188
                Affiliations
                [ 1 ] Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center CHA University Seongnam South Korea
                [ 2 ] Department of Biomedical Science, The Graduate School CHA University Seongnam South Korea
                [ 3 ] Department of Pathology, CHA Bundang Medical Center CHA University Seongnam South Korea
                [ 4 ] Department of Surgery, CHA Bundang Medical Center CHA University Seongnam South Korea
                [ 5 ] Division of Medical Oncology, Department of Internal Medicine Yonsei University College of Medicine Seoul South Korea
                Author notes
                [*] [* ] Correspondence to: Yong Wha Moon, MD, PhD, Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam‐si, Gyeonggi‐do, 463‐712, South Korea, Tel.: +82‐10‐2825‐6357, Fax: +82‐31‐780‐3929, E‐mail: ymoon@ 123456cha.ac.kr
                Author information
                https://orcid.org/0000-0003-2144-0577
                https://orcid.org/0000-0002-2153-1420
                Article
                IJC32020
                10.1002/ijc.32020
                6767051
                30478914
                26d0f74a-320d-4239-a2d4-bdc0ec147b28
                © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 01 September 2018
                : 06 November 2018
                : 19 November 2018
                Page count
                Figures: 2, Tables: 0, Pages: 10, Words: 8587
                Funding
                Funded by: Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea
                Funded by: National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP)
                Award ID: NRF‐2017R1C1B2003618
                Categories
                Mini Review
                Mini Review
                Custom metadata
                2.0
                ijc32020
                1 September 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:30.09.2019

                Oncology & Radiotherapy
                cdk4/6,estrogen receptor‐positive breast cancer,drug resistance
                Oncology & Radiotherapy
                cdk4/6, estrogen receptor‐positive breast cancer, drug resistance

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