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      Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines

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          Abstract

          Background

          Osimertinib is a third-generation EGFR-TKI with a high selective potency against T790M-mutant NSCLC patients. Considering that osimertinib can lead to enhanced HER-2 expression on cell surface and HER-2 overexpression is a mechanism of resistance to osimertinib, this study was addressed to investigate the potential of combining osimertinib with trastuzumab emtansine (T-DM1) in order to improve the efficacy of osimertinib and delay or overcome resistance in NSCLC cell lines with EGFR activating mutation and with T790M mutation or HER-2 amplification.

          Methods

          The effects of osimertinib combined with T-DM1 on cell proliferation, cell cycle, cell death, antibody-dependent cell-mediated cytotoxicity (ADCC), and acquisition of osimertinib resistance was investigated in PC9, PC9-T790M and H1975 cell lines. The potential of overcoming osimertinib resistance with T-DM1 was tested in a PC9/HER2c1 xenograft model.

          Results

          T-DM1 exerted an additive effect when combined with osimertinib in terms of inhibition of cell proliferation, cell death and ADCC induction in PC9, PC9-T790M and H1975 cell lines. Combining osimertinib and T-DM1 using different schedules in long-term growth experiments revealed that the appearance of osimertinib-resistance was prevented in PC9-T790M and delayed in H1975 cells when the two drugs were given together. By contrast, when osimertinib was followed by T-DM1 an antagonistic effect was observed on cell proliferation, cell death and resistance acquisition. In xenograft models, we demonstrated that HER-2 amplification was associated with osimertinib-resistance and that T-DM1 co-administration is a potential strategy to overcome this resistance.

          Conclusions

          Our data suggest that concomitant treatment with osimertinib and T-DM1 may be a promising therapeutic strategy for EGFR-mutant NSCLC.

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          Most cited references 15

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          Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations.

          To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations.
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            Targeting HER2 in the treatment of non-small cell lung cancer.

            Oncogenic driver mutations have emerged as major treatment targets for molecular therapies in a variety of cancers. HER2 positivity has been well-studied in breast cancer, but its importance is still being explored in non-small cell lung cancer (NSCLC). Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for gene mutations. The prognostic and predictive significance of these tests remain to be validated, with an emerging association between HER2 gene mutations and response to HER2 targeted therapies. Despite the assay used to determine the HER2 status of lung tumors, all patients with advanced HER2 positive lung adenocarcinoma should be evaluated for treatment with targeted agents. Several clinical approaches for inclusion of these drugs into patient treatment plans exist, but there is no defined algorithm specific to NSCLC.
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              Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report

               Lin Li,  Hui Wang,  Chao Li (2017)
              AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months treatment of AZD9291 with hepatic metastasis. Re-biopsy of the hepatic lesion showed histopathology transformation to small cell lung cancer, which harbored EGFR exon19 deletion. Therefore, small cell carcinoma transformation is one of potential resistance mechanisms to AZD9291 and regimen for small cell carcinoma may be one of the treatment options.
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                Author and article information

                Contributors
                silvia.lamonica@unipr.it
                daniele.cretella@nemo.unipr.it
                mara.bonelli@unipr.it
                claudia.fumarola@unipr.it
                andrea.cavazzoni@unipr.it
                graziana.digiacomo@unipr.it
                lisa.flammini@unipr.it
                elisabetta.barocelli@unipr.it
                rominari@ao.pr.it
                nnaldi@ao.pr.it
                piergiorgio.petronini@unipr.it
                mtiseo@ao.pr.it
                roberta.alfieri@unipr.it , mtiseo@ao.pr.it
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                4 December 2017
                4 December 2017
                2017
                : 36
                Affiliations
                [1 ]ISNI 0000 0004 1758 0937, GRID grid.10383.39, Department of Medicine and Surgery, , University of Parma, ; Parma, Italy
                [2 ]ISNI 0000 0004 1758 0937, GRID grid.10383.39, Food and Drug Department, , University of Parma, ; Parma, Italy
                [3 ]GRID grid.411482.a, Division of Medical Oncology, , University Hospital of Parma, ; Parma, Italy
                Article
                653
                10.1186/s13046-017-0653-7
                5716361
                29202823
                © The Author(s). 2017

                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.

                Funding
                Funded by: AstraZeneca Italia
                Award ID: n.a.
                Award Recipient :
                Funded by: Associazione Augusto per la Vita
                Award ID: n.a.
                Award Recipient :
                Funded by: Associazione Noi per Loro onlus
                Award ID: n.a.
                Award Recipient :
                Funded by: A.VO.PRO.RI.T
                Award ID: n.a.
                Award Recipient :
                Funded by: Associazione Marta Nurizzo
                Award ID: n.A.
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy

                t-dm1, tki-resistance, osimertinib, egfr, nsclc

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