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      Cigarette smoke-induced LKB1/AMPK pathway deficiency reduces EGFR TKI sensitivity in NSCLC

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          Abstract

          Smoker patients with non-small cell lung cancer (NSCLC) have poorer prognosis and survival than those without smoking history. However, the mechanisms underlying the low response rate of those patients to EGFR tyrosine kinase inhibitors (TKIs) are not well understood. Here we report that exposure to cigarette smoke extract enhances glycolysis and attenuates AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR; this in turn reduces the sensitivity of NSCLC cells with wild-type EGFR (EGFR WT) to EGFR TKI by repressing expression of liver kinase B1 (LKB1), a master kinase of the AMPK subfamily, via CpG island methylation. In addition, LKB1 expression is correlated positively with sensitivity to TKI in patients with NSCLC. Moreover, combined treatment of EGFR TKI with AMPK activators synergistically increases EGFR TKI sensitivity. Collectively, the current study suggests that LKB1 may serve as a marker to predict EGFR TKI sensitivity in smokers with NSCLC carrying EGFR WT and that the combination of EGFR TKI and AMPK activator may be a potentially effective therapeutic strategy against NSCLC with EGFR WT.

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          Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas.

          Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I-II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection. ©2011 AACR.
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            Targeting cellular metabolism to improve cancer therapeutics

            The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metabolism may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metabolism in therapeutic resistance, which is a highly clinical relevant area in cancer metabolism research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metabolism and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.
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              Epidermal growth factor receptor mutations in lung cancer.

              The development and clinical application of inhibitors that target the epidermal growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. We review the results of genetic, biochemical and clinical studies focused on somatic mutations of EGFR that are associated with the phenomenon of oncogene addiction, describing 'oncogenic shock' as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours and devising strategies to circumvent their rapid acquisition of resistance to targeted kinase inhibitors are essential to the successful use of targeted therapies in common epithelial cancers.
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                Author and article information

                Contributors
                chesttu@gmail.com
                mhung@cmu.edu.tw
                whuang@mail.cmu.edu.tw
                Journal
                Oncogene
                Oncogene
                Oncogene
                Nature Publishing Group UK (London )
                0950-9232
                1476-5594
                17 December 2020
                17 December 2020
                2021
                : 40
                : 6
                : 1162-1175
                Affiliations
                [1 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, Graduate Institute of Basic Medical Science, , China Medical University, ; Taichung, 404 Taiwan
                [2 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Molecular and Cellular Oncology, , The University of Texas MD Anderson Cancer Center, ; Houston, TX 77030 USA
                [3 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, Graduate Institute of Biomedical Sciences, , China Medical University, ; Taichung, 404 Taiwan
                [4 ]GRID grid.411508.9, ISNI 0000 0004 0572 9415, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, , China Medical University Hospital, ; Taichung, 404 Taiwan
                [5 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, School of Medicine, , China Medical University, ; Taichung, 404 Taiwan
                [6 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, Department of Respiratory Therapy, , China Medical University, ; Taichung, 404 Taiwan
                [7 ]Taiwan Clinical Trial Consortium for Lung Diseases (TCoC), Taichung, 404 Taiwan
                [8 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, Department of Health Services Administration, , China Medical University, ; Taichung, 406 Taiwan
                [9 ]GRID grid.411508.9, ISNI 0000 0004 0572 9415, Center for Molecular Medicine, , China Medical University Hospital, ; Taichung, 404 Taiwan
                [10 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, Department of Biomedical Imaging and Radiological Science, , China Medical University, ; Taichung, 404 Taiwan
                [11 ]Division of Family Medicine, Physical Examination Center, and Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, 302 Taiwan
                [12 ]GRID grid.452796.b, ISNI 0000 0004 0634 3637, Department of Plastic Surgery, and Innovation Research Center, , Show Chwan Memorial Hospital, ; Changhua, 500 Taiwan
                [13 ]GRID grid.260770.4, ISNI 0000 0001 0425 5914, Department of Biomedical Imaging and Radiological Sciences, , National Yang-Ming University, ; Taipei, 112 Taiwan
                [14 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, The Ph.D. Program for Cancer Biology and Drug Discovery, , China Medical University, ; Taichung, 404 Taiwan
                [15 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, Institute of New Drug Development, , China Medical University, ; Taichung, 404 Taiwan
                [16 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, Drug Development Center, Research Center for Cancer Biology, , China Medical University, ; Taichung, 404 Taiwan
                [17 ]GRID grid.252470.6, ISNI 0000 0000 9263 9645, Department of Biotechnology, , Asia University, ; Taichung, 413 Taiwan
                [18 ]GRID grid.254145.3, ISNI 0000 0001 0083 6092, Chinese Medicine Research Center, , China Medical University, ; Taichung, 404 Taiwan
                [19 ]GRID grid.411641.7, ISNI 0000 0004 0532 2041, Institute of Medicine, , Chung Shan Medical University, ; Taichung, 402 Taiwan
                [20 ]GRID grid.411645.3, ISNI 0000 0004 0638 9256, Division of Thoracic Surgery, Department of Surgery, , Chung Shan Medical University Hospital, ; Taichung, 402 Taiwan
                [21 ]GRID grid.260542.7, ISNI 0000 0004 0532 3749, Department of Life Sciences and Ph.D. Program in Translational Medicine, , National Chung Hsing University, ; Taichung, 402 Taiwan
                [22 ]GRID grid.260542.7, ISNI 0000 0004 0532 3749, The IEGG and Animal Biotechnology Center, , National Chung Hsing University, ; Taichung, 402 Taiwan
                Author information
                http://orcid.org/0000-0002-8217-1692
                http://orcid.org/0000-0002-9745-1726
                http://orcid.org/0000-0003-2461-9150
                http://orcid.org/0000-0002-8126-6171
                http://orcid.org/0000-0003-4317-4740
                http://orcid.org/0000-0001-6467-8716
                Article
                1597
                10.1038/s41388-020-01597-1
                7878190
                33335306
                a8b0fb1f-f2c4-44dc-8ded-50a6d27cc8cf
                © The Author(s) 2020

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 July 2020
                : 18 November 2020
                : 30 November 2020
                Funding
                Funded by: the Ministry of Science Technology, Taiwan (MOST 108-2314-B-039-056 and MOST 108-2314-B-039-053) China Medical University (CMU106-ASIA-18 and CMU107-TU-06) China Medical University Hospital (DMR-107-023 and DMR-108-021)
                Funded by: FundRef https://doi.org/10.13039/100010002, Ministry of Education (Ministry of Education, Republic of China (Taiwan));
                Funded by: the Ministry of Education (The International Co-cultivation of Talent)
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                © Springer Nature Limited 2021

                Oncology & Radiotherapy
                cancer metabolism,non-small-cell lung cancer,predictive markers
                Oncology & Radiotherapy
                cancer metabolism, non-small-cell lung cancer, predictive markers

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