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Chun-Hua Dai, Yang Shu, Ping Chen, Jian-Nong Wu, Li-Haun Zhu, Rong-Xia Yuan, Wei-Guo Long, Yu-Min Zhu, Jian Li
Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib and gefitinib, is a major clinical problem in the treatment of patients with non-small cell lung cancer (NSCLC). YM155 is a survivin small molecule inhibitor and has been demonstrated to induce cancer cell apoptosis and autophagy. EGFR-TKIs have been known to induce cancer cell autophagy. In this study, we showed that YM155 markedly enhanced the sensitivity of erlotinib to EGFR-TKI resistant NSCLC cell lines H1650 (EGFR exon 19 deletion and PTEN loss) and A549 (EGFR wild type and KRAS mutation) through inducing autophagy-dependent apoptosis and autophagic cell death...
October 10, 2018: Biochimica et biophysica acta. Molecular basis of disease
Shengyu Zhou, Xingsheng Hu, Yan Wang, Junling Li, Liqiang Zhou, Xuezhi Hao, Yutao Liu, Yuankai Shi
AIM: Most epidermal growth factor receptor (EGFR) gene mutations affecting exon 19 (inframe deletions; 19 Del) and 21 (L858R), while the rest (referred as uncommon EGFR mutation) have not been fully described due to their rarity. Here we present a retrospective study that investigated clinical characteristics and outcome of patients with different EGFR mutations. METHODS: We retrospectively analyzed the EGFR mutation pattern and its association with clinical-pathological characteristics from 100 cases of nonsmall-cell lung cancer (NSCLC) harboring EGFR mutations, and compiled the genotype response data for NSCLC patients with common and uncommon EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs)...
October 11, 2018: Asia-Pacific Journal of Clinical Oncology
Naoya Nishioka, Tadaaki Yamada, Sachi Harita, Soichi Hirai, Yuki Katayama, Takayuki Nakano, Naoko Okura, Nobuyo Tamiya, Yoshiko Kaneko, Junji Uchino, Koichi Takayama
NSCLC patients with EGFR mutations respond to EGFR-TKIs; however, the management of refractory tumors to EGFR-TKIs remains unclear. We demonstrated that repeated genetic testing might be useful for detecting resistance mechanisms as well as for decision-making in EGFR mutated NSCLC patients, following the emergence of resistance to the initial EGFR-TKIs. A 69-year-old man was diagnosed with lung adenocarcinoma with an EGFR exon 19 deletion. After tumor re-growth treated with erlotinib and chemotherapy, he was diagnosed with an SCLC transformation and administered chemotherapy to treat the SCLC...
2018: Respiratory Medicine Case Reports
Kimio Yonesaka, Naoki Takegawa, Satomi Watanabe, Koji Haratani, Hisato Kawakami, Kazuko Sakai, Yasutaka Chiba, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Kazuto Nishio, Kazuhiko Nakagawa
EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 antibody-drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model...
October 9, 2018: Oncogene
Ping Zhang, Xin Nie, Bing Wang, Lin Li
Acquired resistance inevitably occurs after initial treatment with first-generation EGFR-tyrosine kinase inhibitors (TKIs). Several mechanisms have been identified, including EGFR T790M mutation and HER2 amplification. Herein, we present the case of a patient who progressed on first-generation EGFR-TKIs and developed EGFR T790M mutation, HER2 amplification, and HER2 mutation. The administration of single-agent osimertinib yielded an inconsistent response, with worsened pleural effusion and a reduction to lung metastases, but remarkably, a partial response was achieved after four weeks of treatment with combined osimertinib and afatinib, with grade 1 rash and grade 2 diarrhea...
October 8, 2018: Thoracic Cancer
Akiko Takahashi, Masahiro Seike, Mika Chiba, Satoshi Takahashi, Shinji Nakamichi, Masaru Matsumoto, Susumu Takeuchi, Yuji Minegishi, Rintaro Noro, Shinobu Kunugi, Kaoru Kubota, Akihiko Gemma
Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs...
October 5, 2018: Scientific Reports
Rong Wang, Shunli Peng, Xiaojuan Zhang, Zhenming Wu, Hezhen Duan, Yawei Yuan, Wei Wang
Resistance to radiotherapy and to EGFR tyrosine kinase inhibitors (EGFR-TKIs), as well as therapy-related lung toxicity, are serious problems in the treatment of lung cancer. NF-κB has been reported to be associated with radioresistance. Therefore, we evaluated its effects on sensitivity to irradiation and to EGFR-TKIs; irradiation-induced lung toxicity; and the effects of irradiation on sensitivity to EGFR-TKIs. We used IKKβ inhibitor IMD 0354 or p65 depletion to explore their effects on sensitivity to irradiation and to EGFR-TKIs in vitro and in vivo...
October 5, 2018: International Journal of Cancer. Journal International du Cancer
Eiji Iwama, Kazuko Sakai, Koichi Azuma, Daijiro Harada, Kaname Nosaki, Katsuyuki Hotta, Makoto Nishio, Takayasu Kurata, Tatsuro Fukuhara, Hiroaki Akamatsu, Koichi Goto, Takayuki Shimose, Junji Kishimoto, Yoichi Nakanishi, Kazuto Nishio, Isamu Okamoto
Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance-conferring T790M mutation of EGFR in patients with non-small cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next-generation sequencing (NGS)...
October 5, 2018: Cancer Science
Hongge Liang, Xiaoyan Liu, Mengzhao Wang
In recent years, targeted therapy and immunotherapy have played important roles in the treatment of patients with non-small-cell lung cancer (NSCLC). Drugs that target epidermal growth factor receptor (EGFR) mutations (eg, gefitinib, erlotinib, icotinib, and osimertinib) are among the most commonly used targeted therapies. Afatinib is an irreversible second-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI), and the LUX-Lung 3 trial demonstrated the superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment-naïve patients with advanced EGFR mutation adenocarcinoma of the lung...
2018: OncoTargets and Therapy
Ji Li, Li Zhang, Hui Zhu, Wenting Pan, Nasha Zhang, Yankang Li, Ming Yang
Gefitinib is currently one of the mostly used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for treating nonsmall cell lung cancer. However, drug resistance is observed among the majority of patients after initial treatment. Factors that predict treatment prognosis and drug resistance to EGFR-TKIs remain elusive. The objective of this study is to investigate whether leukocyte relative telomere length (RTL) can be used as a prognostic biomarker of EGFR-TKIs therapy. In this study, 369 patients with stage IIIB or IV lung adenocarcinoma were recruited and treated with gefitinib as first-line monotherapy...
October 2, 2018: DNA and Cell Biology
Naohiro Oda, Kastuyuki Hotta, Kiichiro Ninomiya, Daisuke Minami, Eiki Ichihara, Toshi Murakami, Toshihide Yokoyama, Hirohisa Ichikawa, Kenichi Chikamori, Nagio Takigawa, Nobuaki Ochi, Shingo Harita, Yoshinobu Maeda, Katsuyuki Kiura
PURPOSE: The aim of this study was to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration using afatinib in patients with non-small-cell lung cancer (NSCLC) with a sensitive non-T790M EGFR mutation who had received cytotoxic chemotherapy after acquiring resistance to EGFR-TKIs. METHODS: Eligible patients had EGFR-mutant tumors resistant to first- or second-generation EGFR-TKIs and an EGFR-TKI-free period with cytotoxic agents...
October 1, 2018: Cancer Chemotherapy and Pharmacology
Katsuhiro Masago, Fumiko Imamichi, Yoshio Masuda, Noriko Ariga, Kiyomi Fujitomi, Yoko Fukumine, Kana Hatakenaka, Shiro Fujita, Nobuyuki Katakami
Objective: The aim of this study was to evaluate the effectiveness of a rash team management intervention designed by certified nurses, medical physicians, and certified pharmacists. The quality of life (QOL) of patients administered epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) was assessed using the dermatology life quality index (DLQI) and Skindex-29 QOL questionnaires. Methods: A total of 51 patients with nonsmall cell lung cancer who were treated using EGFR-TKIs were examined between November 1, 2014, and October 31, 2015, at the Institute of Biomedical Research and Innovation in Kobe city, Japan...
October 2018: Asia-Pacific Journal of Oncology Nursing
Ken Uchibori, Miyako Satouchi, Naoko Sueoka-Aragane, Yoshiko Urata, Akemi Sato, Fumio Imamura, Takako Inoue, Motoko Tachihara, Kazuyuki Kobayashi, Nobuyuki Katakami, Chiyuki Kokan, Tomonori Hirashima, Kentaro Iwanaga, Masahide Mori, Keisuke Aoe, Satoshi Morita, Shunichi Negoro
OBJECTIVES: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (i.e., EGFR-TKIs) improve the survival of lung cancer patients harboring EGFR mutations. Despite the initial efficacy of EGFR-TKIs, the disease progression caused by acquired resistance to these inhibitors is inevitable. T790M mutations represent a major resistance mechanism to EGFR-TKIs but can be overcome using osimertinib. The IMPRESS trial revealed that the continuation of EGFR-TKI beyond progressive disease (PD) concurrent with platinum-doublet chemotherapy was not beneficial...
October 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Panwen Tian, Ye Wang, Weiya Wang, Yalun Li, Ke Wang, Xiaowei Cheng, Yuan Tang, Han Han-Zhang, Junyi Ye, Shannon Chuai, Weimin Li
INTRODUCTION: De novo T790 M mutation in EGFR has been reported in various studies. However, its genetic characteristics and association with EGFR tyrosine kinase inhibitors (TKIs) treatment response remain poorly studied. METHODS: We retrospectively screened 1228 consecutive non-small cell lung cancer (NSCLC) patients and identified 29 de novo T790 M carriers. Capture-based targeted deep sequencing was conducted on 21 eligible samples as well as a 20-sample cohort with acquired T790 M mutation after EGFR-TKIs treatment...
October 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Bianca van Veggel, Adrianus J de Langen, Sayed Hashemi, Kim Monkhorst, Efraim H Rosenberg, Daniëlle A M Heideman, Teodora Radonic, Egbert F Smit
PURPOSE: Next to secondary epidermal growth factor receptor (EGFR) mutations, cMET amplification plays an important role in mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI) treatment. Crizotinib, a dual ALK and cMET inhibitor, can induce responses in patients with EGFR mutation positive non-small cell lung cancer (NSCLC) that acquire cMET amplification after EGFR TKI treatment. However, little is known about the duration of response and post-progression resistance mechanisms...
October 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Ying Jin, Xun Shi, Jun Zhao, Qiong He, Ming Chen, Junrong Yan, Qiuxiang Ou, Xue Wu, Yang W Shao, Xinmin Yu
INTRODUCTION: Increasing evidence leads to a ratiocination that genetic heterogeneity of the lung adenocarcinoma with EGFR mutations may impact clinical responses and outcomes to EGFR tyrosine kinase inhibitor (TKI) treatments. METHODS: We performed genetic profiling of pre-treatment samples of 69 lung adenocarcinoma patients, including tumor FFPE and cell-free DNA (cfDNA), targeting 416 cancer-related genes using next generation sequencing. We analyzed mutation concordance across sample types and investigated potential mechanisms that confer primary resistance to EGFR-TKIs in patients with short progression-free survival (PFS) versus those with long PFS...
October 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Herbert H Loong, Sui-Chun Sampson Kwan, Tony Shu-Kam Mok, Yat-Ming Lau
Non-small cell lung cancer (NSCLC) harboring epidermal growth receptor (EGFR) mutation has distinct genomic characteristics. Introduction of systemic treatments that specifically targeted actionable EGFR mutations has changed the therapeutic paradigm in this group of patients. Moreover, newer generations of EGFR tyrosine-kinase inhibitors (EGFR-TKIs) with superior pharmacokinetics and pharmacodynamics properties such as dacomitinib and osimertinib, when used in the front-line setting, have shown more favorable treatment outcomes than first-generation EGFR-TKIs...
September 29, 2018: Current Treatment Options in Oncology
Po-Lan Su, Yi-Lin Wu, Wei-Yuan Chang, Chung-Liang Ho, Yau-Lin Tseng, Wu-Wei Lai, Wu-Chou Su, Chien-Chung Lin, Szu-Chun Yang
Introduction: Brain metastases (BM) are common in advanced non-small cell lung cancer (NSCLC), and the prognosis is poor with few therapeutic options. This study evaluated the efficacy of three epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in preventing and treating BM in patients with EGFR mutation-positive advanced NSCLC. Methods: Patients with EGFR mutation-positive advanced NSCLC who visited a tertiary referral center from 1 December 2013 to 30 November 2017 were analyzed retrospectively...
2018: Therapeutic Advances in Medical Oncology
Zofia Piotrowska, Hideko Isozaki, Jochen K Lennerz, Justin F Gainor, Inga T Lennes, Viola W Zhu, Nicolas Marcoux, Mandeep K Banwait, Subba R Digumarthy, Wenjia Su, Satoshi Yoda, Amanda K Riley, Varuna Nangia, Jessica J Lin, Rebecca J Nagy, Richard B Lanman, Dora Dias-Santagata, Mari Mino-Kenudson, A John Iafrate, Rebecca S Heist, Alice T Shaw, Erica K Evans, Corinne Clifford, Sai-Hong I Ou, Beni Wolf, Aaron N Hata, Lecia V Sequist
We present a cohort of 41 patients with osimertinib resistance biopsies, including two with an acquired CCDC6-RET fusion. While RET fusions have been identified in resistant EGFR-mutant NSCLC, their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of RET fusions in an EGFR-mutant cancer, we expressed CCDC6-RET in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR-TKIs. The selective RET inhibitors BLU-667 or cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition...
September 26, 2018: Cancer Discovery
Bin Wu, Xiaohua Gu, Qiang Zhang, Feng Xie
BACKGROUND: The objective of this study was to assess cost and effectiveness of osimertinib in treating newly diagnosed advanced non-small cell lung cancer with an epidermal growth factor receptor (EGFR) mutation from a public payer's perspective in the U.S. and China. MATERIALS AND METHODS: Markov models were developed to compare three treatment strategies: first-line use of osimertinib, first-line use of the standard first-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) followed by the second-line use of osimertinib, and the standard first-generation EGFR-TKI therapy (standard care [SOC])...
September 26, 2018: Oncologist
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