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      Pathological transition as the arising mechanism for drug resistance in lung cancer

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          Abstract

          Despite the tremendous efforts for improving therapeutics of lung cancer patients, its prognosis remains disappointing. This can be largely attributed to the lack of comprehensive understanding of drug resistance leading to insufficient development of effective therapeutics in clinic. Based on the current progresses of lung cancer research, we classify drug resistance mechanisms into three different levels: molecular, cellular and pathological level. All these three levels have significantly contributed to the acquisition and evolution of drug resistance in clinic. Our understanding on drug resistance mechanisms has begun to change the way of clinical practice and improve patient prognosis. In this review, we focus on discussing the pathological changes linking to drug resistance as this has been largely overlooked in the past decades.

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          Most cited references108

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          Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.

          Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non-small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.
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            Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer.

            The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updates on cancer incidence and death rates and trends in these outcomes for the United States. This year's report includes the prevalence of comorbidity at the time of first cancer diagnosis among patients with lung, colorectal, breast, or prostate cancer and survival among cancer patients based on comorbidity level. Data on cancer incidence were obtained from the NCI, the CDC, and the NAACCR; and data on mortality were obtained from the CDC. Long-term (1975/1992-2010) and short-term (2001-2010) trends in age-adjusted incidence and death rates for all cancers combined and for the leading cancers among men and women were examined by joinpoint analysis. Through linkage with Medicare claims, the prevalence of comorbidity among cancer patients who were diagnosed between 1992 through 2005 residing in 11 Surveillance, Epidemiology, and End Results (SEER) areas were estimated and compared with the prevalence in a 5% random sample of cancer-free Medicare beneficiaries. Among cancer patients, survival and the probabilities of dying of their cancer and of other causes by comorbidity level, age, and stage were calculated. Death rates continued to decline for all cancers combined for men and women of all major racial and ethnic groups and for most major cancer sites; rates for both sexes combined decreased by 1.5% per year from 2001 through 2010. Overall incidence rates decreased in men and stabilized in women. The prevalence of comorbidity was similar among cancer-free Medicare beneficiaries (31.8%), breast cancer patients (32.2%), and prostate cancer patients (30.5%); highest among lung cancer patients (52.9%); and intermediate among colorectal cancer patients (40.7%). Among all cancer patients and especially for patients diagnosed with local and regional disease, age and comorbidity level were important influences on the probability of dying of other causes and, consequently, on overall survival. For patients diagnosed with distant disease, the probability of dying of cancer was much higher than the probability of dying of other causes, and age and comorbidity had a smaller effect on overall survival. Cancer death rates in the United States continue to decline. Estimates of survival that include the probability of dying of cancer and other causes stratified by comorbidity level, age, and stage can provide important information to facilitate treatment decisions. © 2013 American Cancer Society.
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              EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency.

              Trimethylation on H3K27 (H3K27me3) mediated by Polycomb repressive complex 2 (PRC2) has been linked to embryonic stem cell (ESC) identity and pluripotency. EZH2, the catalytic subunit of PRC2, has been reported as the sole histone methyltransferase that methylates H3K27 and mediates transcriptional silencing. Analysis of Ezh2(-/-) ESCs suggests existence of an additional enzyme(s) catalyzing H3K27 methylation. We have identified EZH1, a homolog of EZH2 that is physically present in a noncanonical PRC2 complex, as an H3K27 methyltransferase in vivo and in vitro. EZH1 colocalizes with the H3K27me3 mark on chromatin and preferentially preserves this mark on development-related genes in Ezh2(-/-) ESCs. Depletion of Ezh1 in cells lacking Ezh2 abolishes residual methylation on H3K27 and derepresses H3K27me3 target genes, demonstrating a role of EZH1 in safeguarding ESC identity. Ezh1 partially complements Ezh2 in executing pluripotency during ESC differentiation, suggesting that cell-fate transitions require epigenetic specificity.
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                Author and article information

                Contributors
                nkchenyueqing@163.com
                waiyingyvonnetang@hotmail.com
                Tongxinyuan2013@sibcb.ac.cn
                hbji@sibcb.ac.cn
                Journal
                Cancer Commun (Lond)
                Cancer Commun (Lond)
                Cancer Communications
                BioMed Central (London )
                2523-3548
                1 October 2019
                1 October 2019
                2019
                : 39
                : 53
                Affiliations
                [1 ]ISNI 0000 0004 0467 2285, GRID grid.419092.7, State Key Laboratory of Cell Biology, CAS Center for Excellence on Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, , Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, ; Shanghai, 200031 P. R. China
                [2 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, University of Chinese Academy of Sciences, ; Beijing, 100049 P. R. China
                [3 ]Sunway Medical Centre, 47500 Bandar Sunway, Selangor Malaysia
                [4 ]GRID grid.440637.2, School of Life Science and Technology, , Shanghai Tech University, ; Shanghai, 200120 P. R. China
                Article
                402
                10.1186/s40880-019-0402-8
                6771104
                31570104
                ea24a750-6332-4b20-97e2-a4022f829019
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

                History
                : 4 July 2019
                : 21 September 2019
                Funding
                Funded by: The National Basic Research Program of China
                Award ID: Grant 2017YFA0505501
                Award Recipient :
                Funded by: Strategic Priority Research Program of the Chinese Academy of Sciences
                Award ID: Grant XDB19020201
                Award Recipient :
                Funded by: National Natural Science Foundation of China
                Award ID: Grants 81430066
                Award ID: 91731314
                Award ID: 31621003
                Award ID: 81872312
                Award ID: 81871875
                Award ID: 81802279
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                lung cancer,drug resistance,pathological transition
                lung cancer, drug resistance, pathological transition

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