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https://www.readbyqxmd.com/read/30537950/the-impact-of-the-tumor-shrinkage-by-initial-egfr-inhibitors-according-to-the-detection-of-egfr-t790m-mutation-in-patients-with-non-small-cell-lung-cancer-harboring-egfr-mutations
#1
Akihiro Yoshimura, Tadaaki Yamada, Naoko Okura, Takayuki Takeda, Wataru Furutani, Yutaka Kubota, Shinsuke Shiotsu, Osamu Hiranuma, Naoya Nishioka, Yusuke Chihara, Nobuyo Tamiya, Yoshiko Kaneko, Junji Uchino, Koichi Takayama
BACKGROUND: The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. However, little is known about the population of NSCLC patients who develop acquired resistance due to the T790M mutation. In this study, we focused on the emergence of the T790M mutation and analyzed patients refractory to initial EGFR-TKIs with successful re-biopsy samples...
December 11, 2018: BMC Cancer
https://www.readbyqxmd.com/read/30537515/targeting-pkc%C3%AE-as-a-therapeutic-strategy-against-heterogeneous-mechanisms-of-egfr-inhibitor-resistance-in-egfr-mutant-lung-cancer
#2
Pei-Chih Lee, Yueh-Fu Fang, Hirohito Yamaguchi, Wei-Jan Wang, Tse-Ching Chen, Xuan Hong, Baozhen Ke, Weiya Xia, Yongkun Wei, Zhengyu Zha, Yan Wang, Han-Pin Kuo, Chih-Wei Wang, Chih-Yen Tu, Chia-Hung Chen, Wei-Chien Huang, Shu-Fen Chiang, Lei Nie, Junwei Hou, Chun-Te Chen, Longfei Huo, Wen-Hao Yang, Rong Deng, Katsuya Nakai, Yi-Hsin Hsu, Shih-Shin Chang, Tai-Jan Chiu, Jun Tang, Ran Zhang, Li Wang, Bingliang Fang, Ting Chen, Kwok-Kin Wong, Jennifer L Hsu, Mien-Chie Hung
Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation...
December 10, 2018: Cancer Cell
https://www.readbyqxmd.com/read/30536780/prospective-exosome-focused-translational-research-for-afatinib-study-of-non-small-cell-lung-cancer-patients-expressing-egfr-extra-study
#3
Yusuke Okuma, Kei Morikawa, Hisashi Tanaka, Takuma Yokoyama, Hidetoshi Itani, Kazuya Horiuchi, Hideyuki Nakagawa, Nobumasa Takahashi, Akihiro Bessho, Kenzo Soejima, Kazuma Kishi, Akira Togashi, Yae Kanai, Koji Ueda, Katsuhisa Horimoto, Noriyuki Matsutani, Nobuhiko Seki
Patients with EGFR-mutated non-small cell lung cancer (NSCLC) exhibit resistance to EGFR-tyrosine kinase inhibitors (TKIs) within 9-14 months of therapy. Recently, EGFR-mutated NSCLC has demonstrated the potential for heterogeneity; therefore, the manner of clonal heterogeneity may impact the duration of progression-free and overall survival and other parameters affecting EGFR-TKI treatment efficacy. However no predictive biomarker of these favorable treatment efficacies has been identified to date. The exosome-focused translational research for afatinib (EXTRA) study aims to identify a novel predictive biomarker and a resistance marker for afatinib by analyzing data from association studies of the clinical efficacy of afatinib and four "OMICs" (genomics, proteomics, epigenomics, and metabolomics) using peripheral blood from patients treated with afatinib...
December 8, 2018: Thoracic Cancer
https://www.readbyqxmd.com/read/30527179/effects-of-secondary-egfr-mutations-on-resistance-against-upfront-osimertinib-in-cells-with-egfr-activating-mutations-in-vitro
#4
Masaya Nishino, Kenichi Suda, Yoshihisa Kobayashi, Shuta Ohara, Toshio Fujino, Takamasa Koga, Masato Chiba, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Tetsuya Mitsudomi
OBJECTIVES: Non-small cell lung cancers (NSCLCs) that harbor activating mutations for epidermal growth factor receptor (EGFR) show remarkable initial response to EGFR-tyrosine kinase inhibitors (TKIs), but inevitably acquire resistance, half of which are due to a T790 M secondary mutation when first-generation (1 G) or 2 G EGFR-TKIs are used. Osimertinib, a 3 G EGFR-TKI, is a standard of care in this situation, but eventually also evokes resistance, reportedly due to some tertiary EGFR mutations...
December 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/30522449/different-mutational-characteristics-of-the-subsets-of-egfr-tyrosine-kinase-inhibitor-sensitizing-mutation-positive-lung-adenocarcinoma
#5
Eun Young Kim, Arum Kim, Gaeun Lee, Hangsuck Lee, Yoon Soo Chang
BACKGROUND: A subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved. METHODS: Targeted sequencing using a custom panel containing 70 cancer-related genes were performed from 73 cases of lung adenocarcinoma with mEGFR (study cohort). In parallel, publicly available data of 47 TCGA-LUAD cases with mEGFR (LUAD cohort) were extracted from the GDC data portal and analyzed by non-negative matrix factorization using the Maftools package...
December 6, 2018: BMC Cancer
https://www.readbyqxmd.com/read/30521971/egfr-mutant-sclc-exhibits-heterogeneous-phenotypes-and-resistance-to-common-antineoplastic-drugs
#6
Chih-An Lin, Sung-Liang Yu, Hsuan-Yu Chen, Huei-Wen Chen, Shr-Uen Lin, Chia-Ching Chang, Chong-Jen Yu, Pan-Chyr Yang, Chao-Chi Ho
INTRODUCTION: Approximately 5% of patients with EGFR-activating mutations acquire EGFR-TKIs resistance through SCLC transformation. However, the reason for the poor outcome and the molecular basis of EGFR-mutant SCLC that has transformed from adenocarcinoma remain unclear. METHODS: In this study, we established 2 EGFR-mutant SCLC cell lines from lung adenocarcinoma patients after failed EGFR-TKI treatment to investigate their molecular basis and potential therapeutic strategies in the hope of improving patient outcome...
December 3, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/30506897/the-effects-of-switching-egfr-tki-treatments-for-nonsmall-cell-lung-cancer-because-of-adverse-events
#7
Yoshihiko Sakata, Kodai Kawamura, Naoki Shingu, Shigeo Hiroshige, Yuko Yasuda, Yoshitomo Eguchi, Keisuke Anan, Junpei Hisanaga, Tatsuya Nitawaki, Aiko Nakano, Kazuya Ichikado
BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used to treat patients with nonsmall cell lung cancer (NSCLC) and EGFR driver mutations. Although some patients discontinued these treatments because of adverse events, it is unclear whether switching EGFR-TKI because of adverse events provides a benefit. METHODS: This retrospective study evaluated data from 22 patients with EGFR mutation-positive NSCLC who received at least two EGFR-TKIs that were switched because of adverse events (March 2011 to September 2017)...
December 2, 2018: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/30505497/mir-497-may-enhance-the-sensitivity-of-non-small-cell-lung-cancer-cells-to-gefitinib-through-targeting-the-insulin-like-growth-factor-1-receptor
#8
Wei Ma, Weiye Feng, Jie Tan, Airu Xu, Yudong Hu, Lanlan Ning, Yanhong Kang, Liuqian Wang, Ziwen Zhao
Background: Recently, studies have demonstrated that microRNA-497 (miR-497) plays an important role in modulating tumor cell sensitivity to chemotherapeutic drugs; however, its role in cellular resistance to the effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in treatment of non-small cell lung cancer (NSCLC) is not fully understood. In this study, we explored the potential of miR-497 in targeting the insulin-like growth factor-1 receptor (IGF-1R) signaling pathways to overcome gefitinib resistance...
October 2018: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/30485437/clinical-outcomes-and-secondary-epidermal-growth-factor-receptor-egfr-t790m-mutation-among-first-line-gefitinib-erlotinib-and-afatinib-treated-non-small-cell-lung-cancer-patients-with-activating-egfr-mutations
#9
Yen-Ting Lin, Jin-Shing Chen, Wei-Yu Liao, Chao-Chi Ho, Chia-Lin Hsu, Ching-Yao Yang, Kuan-Yu Chen, Jih-Hsiang Lee, Zhong-Zhe Lin, Jin-Yuan Shih, James Chih-Hsin Yang, Chong-Jen Yu
Gefitinib, erlotinib and afatinib are approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first-line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians' choice...
November 28, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/30483795/dual-blockade-of-egfr-tyrosine-kinase-using-osimertinib-and-afatinib-eradicates-egfr%C3%A2-mutant-ba-f3-cells
#10
Kimio Yonesaka, Yoshihisa Kobayashi, Hidetoshi Hayashi, Yasutaka Chiba, Tetsuya Mitsudomi, Kazuhiko Nakagawa
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs) are efficacious drugs for non‑small cell lung cancers (NSCLCs) with EGFR‑activating mutations. Afatinib, a second‑generation EGFR‑TKI and osimertinib, a third‑generation EGFR‑TKI, are both standard therapies for patients with these types of cancer. Each drug possesses distinct binding sites for the tyrosine kinase domain of EGFR. The present study examined the efficacy of single and combination TKI therapy using in vitro growth inhibition assays of Ba/F3 cells with an EGFR‑activating Del19 mutation...
November 22, 2018: Oncology Reports
https://www.readbyqxmd.com/read/30481207/multiple-configurations-of-egfr-exon-20-resistance-mutations-after-first-and-third-generation-egfr-tki-treatment-affect-treatment-options-in-nsclc
#11
Michael E Goldberg, Meagan Montesion, Lauren Young, James Suh, Joel Greenbowe, Mark Kennedy, Giuseppe Giaccone, Wallace L Akerley, Afshin Dowlati, Benjamin C Creelan, James K Hicks, Paul J Hesketh, Karen L Kelly, Jonathan W Riess, Vincent A Miller, Philip J Stephens, Garrett M Frampton, Siraj Ali, Jeffrey P Gregg, Lee A Albacker
After sequential treatment with first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), EGFR-mutant non-small cell lung cancers frequently harbor multiple resistance mutations in exon 20 of EGFR including T790M, mediating resistance to first-generation TKIs, and at codons 792, 796, or 797 mediating resistance to third-generation TKIs. However, whether these resistance mutations are in cis or trans has therapeutic implications for patients. We analyzed a cohort of 29 patients with NSCLC harboring EGFR mutations at codons 792, 796, or 797 to establish the configuration of these mutations...
2018: PloS One
https://www.readbyqxmd.com/read/30480362/cd146-mediated-acquisition-of-stemness-phenotype-enhances-tumor-invasion-and-metastasis-after-egfr-tki-resistance-in-lung-cancer
#12
Fan Zhang, Jia Wang, Xiaobo Wang, Nan Wei, Haiyang Liu, Xiaoju Zhang
INTRODUCTION: Tumors are more likely to metastasize after development of resistance to EGFR TKIs. CD146 is a multi-functional molecule and is implicated in tumor invasion and metastasis; however, its role in lung cancer has not been clearly established. OBJECTIVE: Here we aimed to explore the relationship between CD146-pathway and stem cell phenotype after EGFR-TKI resistance in lung cancer. METHODS: EGFR-TKI resistance cell lines were established by exposing parental cells to Erlotinib/Gefitinib...
November 27, 2018: Clinical Respiratory Journal
https://www.readbyqxmd.com/read/30473385/impact-of-exon-19-deletion-subtypes-in-egfr-mutant-metastatic-non-small-cell-lung-cancer-treated-with-first-line-tyrosine-kinase-inhibitors
#13
Sabrina Rossi, Luca Toschi, Giovanna Finocchiaro, Vincenzo Di Noia, Maria Bonomi, Eleonora Cerchiaro, Giovanni Luca Ceresoli, Giordano Domenico Beretta, Ettore D'Argento, Armando Santoro
BACKGROUND: Common epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs. PATIENTS AND METHODS: In this retrospective analysis, 106 patients with metastatic NSCLC harboring EGFR exon 19 deletions and treated with first-line TKIs were included...
November 2, 2018: Clinical Lung Cancer
https://www.readbyqxmd.com/read/30473379/integrin-linked-kinase-ilk-and-src-homology-2-domain-containing-phosphatase-2-shp2-novel-targets-in-egfr-mutation-positive-non-small-cell-lung-cancer-nsclc
#14
Niki Karachaliou, Andres Felipe Cardona, Jillian Wilhelmina Paulina Bracht, Erika Aldeguer, Ana Drozdowskyj, Manuel Fernandez-Bruno, Imane Chaib, Jordi Berenguer, Mariacarmela Santarpia, Masaoki Ito, Jordi Codony-Servat, Rafael Rosell
BACKGROUND: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation...
November 22, 2018: EBioMedicine
https://www.readbyqxmd.com/read/30471423/stromal-extracellular-matrix-is-a-microenvironmental-cue-promoting-resistance-to-egfr-tyrosine-kinase-inhibitors-in-lung-cancer-cells
#15
Yuanyuan Wang, Ting Zhang, Lixia Guo, Tao Ren, Yanan Yang
The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or -selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes...
November 21, 2018: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/30464688/afatinib-in-advanced-pretreated-non-small-cell-lung-cancer-a-canadian-experience
#16
D A Ezeife, B Melosky, R Tudor, S Lin, A Lau, T Panzarella, N B Leighl
Background: Afatinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki), is approved for first-line therapy in advanced EGFR mutation-positive non-small-cell lung cancer (nsclc) and has previously demonstrated activity after failure of chemotherapy and reversible egfr tkis, with improved response and progression-free survival, compared with placebo. Outcomes in pretreated patients with advanced nsclc receiving afatinib through a Canadian special access program (sap) are reported here...
October 2018: Current Oncology
https://www.readbyqxmd.com/read/30454551/-molecular-mechanism-of-different-signaling-pathways-in-regulating-pd-l1-expression-in-egfr-mutated-lung-adenocarcinoma
#17
Xuefeng Leng, Jiandong Mei, Lunxu Liu
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors were landmarks in the treatment of non-small cell lung cancer (NSCLC). However, the regulation mechanisms of PD-L1 expression were not fully clear in NSCLC patients with EGFR mutations. Multiple signaling pathways may be involved in the tumorigenesis regulation. This paper summarized and reviewed the potential EGFR mutations impacting on PD-L1 expression with aims to the development of strategies on immunochemical therapy for NSCLC...
November 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/30453899/highly-sensitive-detection-of-alk-resistance-mutations-in-plasma-using-droplet-digital-pcr
#18
Ryohei Yoshida, Takaaki Sasaki, Yasuhiro Umekage, Sachie Tanno, Yusuke Ono, Munehiko Ogata, Shinichi Chiba, Yusuke Mizukami, Yoshinobu Ohsaki
BACKGROUND: On-target resistance mechanisms found in one-third of patients receiving anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are secondary ALK mutations in ALK-rearranged non-small cell lung cancer (NSCLC). There are large variations in the resistant mutations, unlike the epithelial growth factor receptor (EGFR) T790 M seen with the use of EGFR-TKIs. Liquid biopsy approaches using cell-free DNA (cfDNA) are used for screening and monitoring of mutations in NSCLC...
November 19, 2018: BMC Cancer
https://www.readbyqxmd.com/read/30445769/mechanism-of-resistance-to-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-and-a-potential-treatment-strategy
#19
REVIEW
Tatsuya Nagano, Motoko Tachihara, Yoshihiro Nishimura
Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR -mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR -mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance...
November 15, 2018: Cells
https://www.readbyqxmd.com/read/30429037/three-new-disease-progression-modes-in-nsclc-patients-after-egfr-tki-treatment-by-next-generation-sequencing-analysis
#20
Yuqing Wei, Kaikai Shen, Tangfeng Lv, Xianghai Wang, Chuling Li, Hang Fan, Yanling Lv, Hongbing Liu, Yong Song
INTRODUCTION: Most non-small-cell lung cancer (NSCLC) patients who exhibit good clinical responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) will inevitably develop disease progression. Herein, through next-generation sequencing (NGS), we aimed to investigate three new disease-progression modes of NSCLC patients after EGFR-TKI treatment. MATERIALS AND METHODS: Patients with sensitive EGFR-mutations who acquired resistance to EGFR-TKIs and whose tissues were subjected to post-progression NGS were enrolled...
November 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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