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Shimamura, Takeshi

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Shimamura

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Takeshi

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Shimamura, Takeshi
Author's Publications: search.filters.isAuthorOfPublication.6f634c2a-97da-4ae9-ba98-94a05bfdc281

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    Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors
    (American Association for Cancer Research (AACR), 2012) Ercan, Dalia; Xu, Chunxiao; Yanagita, Masahiko; Monast, Calixte S.; Pratilas, Christine A.; Montero, Juan; Butaney, Mohit; Shimamura, Takeshi; Sholl, Lynette; Ivanova, Elena; Tadi, Madhavi; Rogers, Andrew; Repellin, Claire; Capelletti, Marzia; Maertens, Ophelia; Goetz, Eva Marie; Letai, Anthony; Garraway, Levi; Lazzara, Matthew J.; Rosen, Neal; Gray, Nathanael; Wong, Kwok-Kin; Janne, Pasi
    The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib resistant EGFR mutant NSCLC patient. In addition, the WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rationale combination therapies that should be evaluated in clinical trials.
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    Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
    (American Association for Cancer Research (AACR), 2013) Akbay, Esra A.; Koyama, S.; Carretero, J.; Altabef, A.; Tchaicha, J. H.; Christensen, Camilla; Mikse, O. R.; Cherniack, Andrew; Beauchamp, Ellen; Pugh, Trevor J.; Wilkerson, M. D.; Fecci, Peter; Butaney, M.; Reibel, J. B.; Soucheray, M.; Cohoon, T. J.; Janne, Pasi; Meyerson, Matthew; Hayes, D. N.; Shapiro, Geoffrey; Shimamura, Takeshi; Sholl, Lynette; Rodig, Scott; Freeman, Gordon; Hammerman, Peter S.; Dranoff, Glenn; Wong, Kwok-Kin
    The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.
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    Early Detection of Erlotinib Treatment Response in NSCLC by 3′-Deoxy-3′-[\(^{18}F\)]-Fluoro-L-Thymidine ([\(^{18}F\)]FLT) Positron Emission Tomography (PET)
    (Public Library of Science, 2008) Ullrich, Roland T.; Zander, Thomas; Neumaier, Bernd; Koker, Mirjam; Waerzeggers, Yannic; Borgman, Christa L.; Tawadros, Samir; Li, Hongfeng; Sos, Martin L.; Backes, Heiko; Wolf, Jürgen; Jacobs, Andreas H.; Thomas, Roman K.; Winkeler, Alexandra; Shimamura, Takeshi; Shapiro, Geoffrey
    Background: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 3′-Deoxy-3′-[\(^{18}F\)]-fluoro-L-thymidine ([\(^{18}F\)]FLT) and 2-[\(^{18}F\)]-fluoro-2-deoxy-D-glucose ([\(^{18}F\)]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [\(^{18}F\)]FLT uptake after only two days of treatment, [\(^{18}F\)]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [\(^{18}F\)]FLT PET but not [\(^{18}F\)]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [\(^{18}F\)]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [\(^{18}F\)]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [\(^{18}F\)]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [\(^{18}F\)]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC.