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      • Record: found
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      CDK4/6 inhibitor palbociclib overcomes acquired resistance to third‐generation EGFR inhibitor osimertinib in non‐small cell lung cancer (NSCLC)

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          Abstract

          Background

          The third‐generation EGFR‐TKI, represented by osimertinib, has been widely used in clinical practice; however, resistance eventually emerges. At present, it remains unclear whether an abnormal cell cycle is involved in acquired resistance, and whether the combination of palbociclib (CDK4/6 inhibitor) and osimertinib can overcome the third‐generation TKI resistance.

          Methods

          We established osimertinib‐resistant cells (H1975 OR) derived from EGFR‐mutant NSCLC cells H1975. Drug effects on cells were assessed with Cell Counting Kit‐8 (CCK8). Protein alterations were detected with western blot analysis. RT‐PCR was used to evaluate the differences of gene mRNA. Cell cycle distribution of H1975 S and H1975 OR cells was compared using flow cytometry.

          Results

          Compared with H1975, the sensitivity of H1975OR to the CDK4/6 inhibitor was increased and the proportion of cells in G1 phase was decreased. The mRNA level of CDK4, CDK 6 and the protein level of CDK4, pRB were increased in H1975OR. In the H1975OR cells, palbociclib significantly increased the proportion of G1 phase cells. The combination of osimertinib and palbociclib synergistically decreased the survival of H1975OR by cell cycle arrest. Combined treatment was found to inhibit the initial phosphorylation of RB by inhibiting the function of CDK4/6, significantly reducing the level of p‐RB, and blocking cell proliferation.

          Conclusions

          An osimertinib acquired resistance cell line (H1975 OR) was successfully established. The expression of cell cycle related genes was altered in H1975OR. The expression of CDK4 and the phosphorylation of Rb, the downstream molecule of CDK4/6, was increased in H1975OR cells. The combination of CDK4/6 inhibitor palbociclib and osimertinib could overcome the acquired resistance of osimertinib.

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          Most cited references 19

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          Targeting CDK4 and CDK6: From Discovery to Therapy.

          Biochemical and genetic characterization of D-type cyclins, their cyclin D-dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16(INK4)over two decades ago revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell-division cycle in a retinoblastoma protein-dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with coinhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy. FDA approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long-sought success. The newest findings herald clinical trials targeting other cancers.
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            Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors.

            We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months.
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              A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma.

              We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a mouse tumor model that closely recapitulates human non-small cell lung carcinoma (NSCLC). Ablation of Cdk4, but not Cdk2 or Cdk6, induces an immediate senescence response only in lung cells that express an endogenous K-Ras oncogene. No such response occurs in lungs expressing a single Cdk4 allele or in other K-Ras-expressing tissues. More importantly, targeting Cdk4 alleles in advanced tumors detectable by computed tomography scanning also induces senescence and prevents tumor progression. These observations suggest that robust and selective pharmacological inhibition of Cdk4 may provide therapeutic benefit for NSCLC patients carrying K-RAS oncogenes. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                lsun1@tmu.edu.cn
                zhongdsh@hotmail.com
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                16 July 2020
                September 2020
                : 11
                : 9 ( doiID: 10.1111/tca.v11.9 )
                : 2389-2397
                Affiliations
                [ 1 ] Department of Oncology Tianjin Medical University General Hospital Tianjin China
                [ 2 ] Tianjin Lung Cancer Institute Tianjin Medical University General Hospital Tianjin China
                [ 3 ] Tianjin Medical University Cancer Institute and Hospital Tianjin China
                Author notes
                [* ] Correspondence

                Diansheng Zhong, Department of Oncology, Tianjin Medical University General Hospital, No.154 Anshan Street, Heping District, Tianjin 300052, China.

                Tel: +86 22 6081 7007

                Fax: +86 22 8723 6114

                Email: zhongdsh@ 123456hotmail.com

                Linlin Sun, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, No.154 Anshan Street, Heping District, Tianjin 300052, China.

                Tel: +86 22 6081 4993

                Fax: +86 22 8723 6114

                Email: lsun1@ 123456tmu.edu.cn

                Article
                TCA13521
                10.1111/1759-7714.13521
                7471056
                32677256
                © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 6, Tables: 1, Pages: 9, Words: 5421
                Product
                Funding
                Funded by: Natural Science Foundation of Tianjin , open-funder-registry 10.13039/501100006606;
                Award ID: 16JCYBJC24400
                Award ID: 17JCYBJC25500
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 31301160
                Award ID: 81972186
                Award ID: 81572268
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                September 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.9 mode:remove_FC converted:03.09.2020

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