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Ji Yeon Kim, Woo Jeong Lee, Ha Young Park, Ahrong Kim, Dong Hoon Shin, Chang Hun Lee
Background: MicroRNAs (miRNAs) are short, non-coding RNAs that mediate post-transcriptional gene regulation. They are commonly deregulated in human malignancies, including non-small cell lung cancer (NSCLC). The aim of this study is to investigate miRNA expression in T790M-mutated NSCLC resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Materials and Methods: Six cases of resected NSCLC harboring the T790M mutation were examined...
August 16, 2018: Journal of Pathology and Translational Medicine
Junjun Li, Xiaomei Liu, Caijun Yuan
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in the treatment of advanced non-small-cell lung cancer (NSCLC) with leptomeningeal metastases (LM); however, a proportion of the patients with resistant tumors do not benefit from EGFR-TKI treatment. In the present study the case of a female patient with advanced lung adenocarcinoma harboring the EGFR L858R mutation (encoded in exon 21) who developed intracranial metastases following treatment with erlotinib after gefitinib failure is reported...
September 2018: Molecular and Clinical Oncology
Xiao Yang, Yu Peng, Xuan Jiang, Xianfeng Lu, Wei Duan, Shiheng Zhang, Nan Dai, Jinlu Shan, Yan Feng, Xuemei Li, Yi Cheng, Yuxin Yang, Laura Baugh, Gianluca Tell, Dong Wang, Mengxia Li
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor-β (TGF-β), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR-TKI responsiveness in NSCLC. METHODS: The protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR-TKI treatment...
August 14, 2018: Cancer Medicine
Mitsuo Sato, Akira Matsui, Yoshie Shimoyama, Norihito Omote, Masahiro Morise, Tetsunari Hase, Ichidai Tanaka, Kojiro Suzuki, Yoshinori Hasegawa
Squamous cell carcinoma (SCC) transformation has been identified as a mechanism of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib, in EGFR-mutated lung cancer. However, whether second- or third-generation TKIs can overcome resistance due to SCC transformation remains unclear. We herein report an EGFR-mutated lung adenocarcinoma undergoing transformation into SCC that exhibited a durable response to afatinib, which is a second-generation irreversible EGFR-TKI...
August 10, 2018: Internal Medicine
M Kimura, F Yasue, E Usami, S Kawachi, M Iwai, M Go, Y Ikeda, T Yoshimura
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib and afatinib are standard first-line treatments for EGFR gene mutation-positive non-small cell lung cancer. The present study aimed to compare the cost-effectiveness of using erlotinib, afatinib or gefitinib. The safety of EGFR-TKIs was also investigated. Expected costs were calculated based on data from patients with advanced EGFR mutation-positive non-small-cell lung cancer who were treated with gefitinib, erlotinib or afatinib...
August 2018: Molecular and Clinical Oncology
Hiroki Sato, Hiromasa Yamamoto, Masakiyo Sakaguchi, Kazuhiko Shien, Shuta Tomida, Tadahiko Shien, Hirokuni Ikeda, Minami Hatono, Hidejiro Torigoe, Kei Namba, Takahiro Yoshioka, Eisuke Kurihara, Yusuke Ogoshi, Yuta Takahashi, Junichi Soh, Shinichi Toyooka
Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines...
August 10, 2018: Cancer Science
Zohra Mraihi, Jihen Ben Amar, Hend Bouacha, Soumaya Rammeh, Lamia Hila
BACKGROUND: Screening mutations in epidermal growth factor receptor (EGFR) to analyze non-small-cell lung cancer (NSCLC) profile is the criterion to choose the best therapeutic strategy. New Oncology guidelines recommend EGFR mutation analysis before prescribing tyrosine kinase inhibitors (TKIs) treatment. Majority of lung cancer patients are diagnosed at advanced stages and generally only small biopsies materials are available for diagnostic and molecular characterization. The aim of this first work is to screen EGFR mutation status in Tunisian NSCLC by mutation-specific immunohistochemistry (IHC) and molecular biology, to estimate the relevance of proposing TKIs as a new therapeutic line...
August 9, 2018: BMC Pulmonary Medicine
Lauren C J Baker, Arti Sikka, Jonathan M Price, Jessica K R Boult, Elise Y Lepicard, Gary Box, Yann Jamin, Terry J Spinks, Gabriela Kramer-Marek, Martin O Leach, Suzanne A Eccles, Carol Box, Simon P Robinson
Background: Overexpression of EGFR is a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Patients with HNSCC who respond to EGFR-targeted tyrosine kinase inhibitors (TKIs) eventually develop acquired resistance. Strategies to identify HNSCC patients likely to benefit from EGFR-targeted therapies, together with biomarkers of treatment response, would have clinical value. Methods: Functional MRI and 18 F-FDG PET were used to visualize and quantify imaging biomarkers associated with drug response within size-matched EGFR TKI-resistant CAL 27 (CALR ) and sensitive (CALS ) HNSCC xenografts in vivo , and pathological correlates sought...
2018: Frontiers in Oncology
Ilaria Attili, Niki Karachaliou, PierFranco Conte, Laura Bonanno, Rafael Rosell
Epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) is a subset of lung cancer with demonstrated response to targeted therapies. However, resistance to the first targeted approach usually occurs within the first year, and it is associated in 50-60% of cases to the T790M resistance mutation. Areas covered: The review provides an overview on the significance of the presence of the T790M mutation, its detection, treatment options and subsequent mechanisms of resistance...
August 14, 2018: Expert Review of Anticancer Therapy
Masashi Fukuoka, Katsuji Yoshioka, Hirohiko Hohjoh
Gefitinib and erlotinib are epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Although EGFR-TKIs are effective as anti-cancer drugs, cancer cells sometimes gain tolerance to the drugs. Previous studies suggested that the fibroblast growth factor receptor (FGFR)-signaling pathway could serve as compensation for the EGFR-signaling pathway inhibited by EGFR-TKIs. Our study further suggested that FGF2, a FGFR ligand, leaked out from naïve cells killed by gefitinib could initiate the FGFR-signaling pathway in surviving cells; i...
2018: PloS One
Satoshi Watanabe, O U Yamaguchi, A I Masumoto, Yuri Maeno, Yosuke Kawashima, Osamu Ishimoto, Shunichi Sugawara, Hirohisa Yoshizawa, Toshiaki Kikuchi, Toshihiro Nukiwa, Kunihiko Kobayashi
BACKGROUND/AIM: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. PATIENTS AND METHODS: We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs...
August 2018: Anticancer Research
Hideaki Takahashi, Mizuho Isogawa
Brain metastases are usual in breast cancer with poor prognosis and few available therapeutic options. The efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) against brain metastases from EGFR mutation-positive non-small cell lung cancer (NSCLC) showed promising antitumor activity, on the other hand, the main treatment of breast cancer brain metastases (BCBMs) is only local therapy such as surgery or radiotherapy. The goal of treatment includes stabilizing or improving neurological function and palliating neurological symptom...
June 2018: Chinese Clinical Oncology
Shan Su, Zhong-Yi Dong, Zhi Xie, Li-Xu Yan, Yu-Fa Li, Jian Su, Si-Yang Liu, Kai Yin, Rui-Lian Chen, Shu-Mei Huang, Zhi-Hong Chen, Jin-Ji Yang, Hai-Yan Tu, Qing Zhou, Wen-Zhao Zhong, Xu-Chao Zhang, Yi-Long Wu
INTRODUCTION: This study evaluated whether tumor expression of programmed death-ligand 1 (PD-L1) could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. METHODS: We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC at the Guangdong Lung Cancer Institute between April 2016 and September 2017 and were not enrolled in clinical studies. The patients' EGFR and PD-L1 statuses were simultaneously evaluated...
July 26, 2018: Journal of Thoracic Oncology
In Ae Kim, Jong Sik Lee, Hee Joung Kim, Wan Seop Kim, Kye Young Lee
BACKGROUND: Although lung adenocarcinoma with activating epidermal growth factor receptor (EGFR) mutations is common in never smokers, one-third of the patients are ever-smokers. We aimed to investigate the effect of cumulative smoking dose(CSD) on clinical outcomes, including progression-free survival (PFS) and overall survival (OS), in patients with EGFR-mutated lung adenocarcinoma receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We retrospectively analyzed 142 patients with EGFR-mutation positive advanced or recurrent lung adenocarcinoma who were administered gefitinib, erlotinib, afatinib, and osimertinib...
July 28, 2018: BMC Cancer
Yuka Kato, Kiichiro Ninomiya, Kadoaki Ohashi, Shuta Tomida, Go Makimoto, Hiromi Watanabe, Kenichiro Kudo, Shingo Matsumoto, Shigeki Umemura, Koichi Goto, Eiki Ichihara, Takashi Ninomiya, Toshio Kubo, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura
The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. Two lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing (NGS)...
July 27, 2018: Cancer Science
Kenichi Suda, Isao Murakami, Hui Yu, Jihye Kim, Aik-Choon Tan, Hiroshi Mizuuchi, Leslie M Rozeboom, Kim Ellison, Christopher J Rivard, Tetsuya Mitsudomi, Fred R Hirsch
Epithelial to mesenchymal transition (EMT) is one of the acquired resistance mechanisms to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung cancers. Since EMT is related to tumor invasion, metastases, and resistance to various treatments, it is important to prevent the emergence of EMT. However, molecular mechanism(s) underlying EMT phenotypic changes, as well as biomarker(s) that predict the emergence of EMT in EGFR-mutated lung cancers are unclear to date. Through the comparison of expression data between isogenic lung cancer cell lines that acquired resistance to EGFR-TKI(s), we identified that high CD44 expression is related to a mesenchymal phenotype, and that sh-RNA-mediated knockdown of CD44 reversed the EMT change...
July 26, 2018: Molecular Cancer Therapeutics
Seonggyu Byeon, Youjin Kim, Sung Won Lim, Jang Ho Cho, Sehoon Park, Jiyun Lee, Jong-Mu Sun, Yoon-La Choi, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Purpose: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFR mutations. Given the rarity of this mutation, its clinical outcomes are not fully established. Materials and Methods: Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy...
July 23, 2018: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Yuan Zhang, Yang-Chun Feng, Hong-Ge Zhu, Ting-Chuan Xiong, Yan-Shen Hou, Jia Song, Wei Jiang, Chang-Jun Zhu
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment for EGFR-mutant nonsmall cell lung cancer (NSCLC) patients. However, studies have reported that not all NSCLC patients harboring kinase domain mutations in epidermal growth factor receptor (EGFR) show significant clinical benefits from EGFR-targeted tyrosine kinase inhibitors (TKIs). Therefore, it is necessary to establish feasible biomarkers to predict the prognosis of EGFR-mutant NSCLC patients treated with EGFR-TKIs...
July 2018: Medicine (Baltimore)
Jia-Zhou Lin, Song-Kun Ma, Sheng-Xi Wu, Shu-Han Yu, Xu-Yuan Li
BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line treatment for nonsmall-cell lung cancer (NSCLC) patients with an activating EGFR mutation. Osimertinib, compared with erlotinib or gefitinib, showed an improvement in progression-free survival (PFS) in a recent trial. The authors compared EGFR TKIs in terms of PFS in a network meta-analysis. METHODS: The PubMed and Embase databases and meeting abstracts were screened for relevant studies between January 2009 and November 2017...
July 2018: Medicine (Baltimore)
Vino T Cheriyan, Hashem Alsaab, Sreeja Sekhar, Jaganathan Venkatesh, Arindam Mondal, Imran Vhora, Samaresh Sau, Magesh Muthu, Lisa A Polin, Edi Levi, Gerold Bepler, Arun K Iyer, Mandip Singh, Arun K Rishi
Non-small cell lung cancers (NSCLC) account for 85% of all lung cancers, and the epidermal growth factor receptor (EGFR) is highly expressed or activated in many NSCLC that permit use of EGFR tyrosine kinase inhibitors (TKIs) as frontline therapies. Resistance to EGFR TKIs eventually develops that necessitates development of improved and effective therapeutics. CARP-1/CCAR1 is an effector of apoptosis by Doxorubicin, Etoposide, or Gefitinib, while CARP-1 functional mimetic (CFM) compounds bind with CARP-1, and stimulate CARP-1 expression and apoptosis...
July 3, 2018: Oncotarget
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