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      Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

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          Abstract

          Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated ( EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

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          Acquired resistance to TKIs in solid tumours: learning from lung cancer.

          The use of advanced molecular profiling to direct the use of targeted therapy, such as tyrosine kinase inhibitors (TKIs) for patients with advanced-stage non-small-cell lung cancer (NSCLC), has revolutionized the treatment of this disease. However, acquired resistance, defined as progression after initial benefit, to targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding and treatment of acquired resistance in NSCLC, focusing on EGFR mutant and ALK rearrangement-positive disease, which may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. Mechanisms of acquired resistance may be pharmacological (that is, failure of delivery of the drug to its target) or biological, resulting from evolutionary selection on molecularly diverse tumours. A number of clinical approaches can maintain control of the disease in the acquired resistance setting, including the use of radiation to treat isolated areas of progression and adding or switching to cytotoxic chemotherapy. Furthermore, novel approaches that have already proven successful include the development of second-generation and third-generation inhibitors and the combination of some of these inhibitors with antibodies directed against the same target. With our increased understanding of the spectrum of acquired resistance, major changes in how we conduct clinical research in this setting are now underway.
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            Genomic and molecular characterization of esophageal squamous cell carcinoma

            Esophageal squamous cell carcinoma (ESCC) is a world-wide prevalent cancer, which is particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified novel significantly mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to previously discovered ones (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Moreover, our approaches uncovered many novel druggable candidates, and XPO1 was further explored as a therapeutic target because of its mutation and protein overexpression. Together, our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.
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              Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.

              Ten percent of North American patients with non-small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                01 July 2019
                July 2019
                : 11
                : 7
                : 923
                Affiliations
                [1 ]Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
                [2 ]Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
                [3 ]Department of Oncology and Palliative Units, Zealand University Hospital, DK-4700 Næstved, Denmark
                [4 ]Department of Clinical Genetics and Pathology, Skåne University Hospital, SE-221 85 Lund, Sweden
                Author notes
                Author information
                https://orcid.org/0000-0002-2283-3535
                Article
                cancers-11-00923
                10.3390/cancers11070923
                6678669
                31266248
                b67a915b-a89f-48e1-861f-9049887db15b
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 April 2019
                : 25 June 2019
                Categories
                Review

                egfr-mutated non-small cell lung cancer,egfr-tki,intrinsic resistance,resistance mechanisms

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