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Egfr-tki treatment for lung cancer

Xilin Sun, Zunyu Xiao, Gongyan Chen, Zhaoguo Han, Yang Liu, Chongqing Zhang, Yingying Sun, Yan Song, Kai Wang, Fang Fang, Xiance Wang, Yanhong Lin, Lili Xu, Liming Shao, Jin Li, Zhen Cheng, Sanjiv Sam Gambhir, Baozhong Shen
Tumor heterogeneity and changes in epidermal growth factor receptor (EGFR) mutation status over time challenge the design of effective EGFR tyrosine kinase inhibitor (TKI) treatment strategies for non-small cell lung cancer (NSCLC). Therefore, there is an urgent need to develop techniques for comprehensive tumor EGFR profiling in real time, particularly in lung cancer precision medicine trials. We report a positron emission tomography (PET) tracer, N -(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-18 F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (18 F-MPG), with high specificity to activating EGFR mutant kinase...
March 7, 2018: Science Translational Medicine
De-Wei Wu, Yao-Chen Wang, Lee Wang, Chih Yi Chen, Huei Lee
Purpose: MicroRNA-630 plays dual roles in apoptosis and drug resistance in human cancers. However, the role of miR-630 in resistance to tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma remains to be elucidated. Methods: Manipulation of miR-630 and its targeted gene YAP1 and/or combination of inhibitor treatments was performed to explore whether low miR-630 could confer TKI resistance due to de-targeting YAP1, and this could decrease proapoptotic protein Bad expression through the miR-630/YAP1/ERK feedback loop...
2018: Theranostics
Bo Zhang, Jianlin Xu, Xueyan Zhang, Ping Gu, Huimin Wang, Shuyuan Wang, Jie Qian, Rong Qiao, Yanwei Zhang, Wenjia Yang, Fangfei Qian, Yan Zhou, Jun Lu, Lele Zhang, Baohui Han
OBJECTIVES: Occasionally, primary 20 T790M/insertion plus sensitive mutations can be detected within a single tumor sample by routine molecular testing, but the optimal clinical management for these patients is unclear. Herein, we determined the optimal treatment strategy for these patients. MATERIALS AND METHODS: From January 2011 to January 2017, patients diagnosed with epidermal growth factor receptor (EGFR) mutation were screened. For these harboring primary 20 T790M/insertion plus sensitive mutations, the effectiveness of the first or third generation tyrosine kinase inhibitors (TKIs) were retrospectively analyzed...
March 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Juan Chen, Jie-da Cui, Xiao-Tong Guo, Xia Cao, Qing Li
Epidermal growth receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for advanced non-small-cell lung cancer (NSCLC) patients with EFGR mutations. However, most patients with NSCLC show acquired resistance to EGFR-TKIs, and low expression of NF1 is a mechanism of EGFR-TKI resistance in lung cancer. However, the mechanism by which NF1 is downregulated in EGFR-TKI-resistant NSCLC is unclear. Here, we found the increased expression of miR-641 in NSCLC cells and human NSCLC samples with resistance to TKI compared to those with sensitive to TKI...
March 1, 2018: Cancer Medicine
Romain Corre, Radj Gervais, Florian Guisier, Louis Tassy, Florent Vinas, Régine Lamy, Gislaine Fraboulet, Laurent Greillier, Helene Doubre, Renaud Descourt, Christos Chouaid, Jean-Bernard Auliac
Objective: To assess efficacy and tolerance of EGFR tyrosine-kinase inhibitors (TKIs) for advanced EGFR-mutated non-small cell lung cancer (NSCLC) in octogenarians. Patients and methods: Patients aged 80 years or older with EGFR-mutated NSCLC treated by EGFR TKI between January 2011 and March 2015 whatever the line of treatment were retrospectively selected. Results: 20 centers retrospectively included 114 patients (women, 77.2%; Caucasians, 98...
February 2, 2018: Oncotarget
Soon Auck Hong, Si-Hyong Jang, Mee-Hye Oh, Sung Joon Kim, Jin-Hyung Kang, Sook-Hee Hong
EGFR tyrosine kinase inhibitor (EGFR TKI) is approved as first-line treatment for advanced-stage EGFR mutant lung adenocarcinoma (LADC). Yes-associated protein 1 (YAP1), a main effector of the Hippo pathway, is associated with adverse prognosis and disruption of EGFR TKI modulation of non-small cell lung cancer. In this study, we demonstrated a prognostic role of YAP1 in EGFR mutant LADC and efficacy of EGFR TKI therapy. A total of 63 patients, including 41 with paired lung cancer specimens before and after EGFR TKI therapy and 22 with non-paired lung cancer specimens prior to EGFR TKI, were enrolled for examination...
February 3, 2018: Pathology, Research and Practice
Po-Hao Feng, Chih-Teng Yu, Kuan-Yuan Chen, Ching-Shan Luo, Shen Ming Wu, Chien-Ying Liu, Lu Wei Kuo, Yao-Fei Chan, Tzu-Tao Chen, Chih-Cheng Chang, Chun-Nin Lee, Hsiao-Chi Chuang, Chiou-Feng Lin, Chia-Li Han, Wei-Hwa Lee, Kang-Yun Lee
Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS)...
January 26, 2018: Oncotarget
Liping Lin, Juanjuan Zhao, Jiazhu Hu, Fuxi Huang, Jianjun Han, Yan He, Xiaolong Cao
Purpose The aim of this study is to evaluate the impact of weight loss at presentation on treatment outcomes of first-line EGFR-tyrosine kinase inhibitors (EGFR-TKI) in EGFR-TKI sensitive mutant NSCLC patients. Methods We retrospectively analyzed the clinical outcomes of 75 consecutive advanced NSCLC patients with EGFR-TKI sensitive mutations (exon 19 deletion or exon 21 L858R) received first-line gefitinib or erlotinib therapy according to weight loss status at presentation in our single center. Results Of 75 EGFR-TKI sensitive mutant NSCLC patients, 49 (65...
2018: Journal of Cancer
Zheng Yang, Kin Yip Tam
Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired resistance inevitably occurs after long-term exposure. More recently, combination therapy has emerged as a promising strategy to overcome this issue. Several experiments have been carried out to evaluate the synergism of combination therapy both in vitro and in vivo . Additionally, many clinical studies have been carried out to investigate the feasibility of treatment with EGFR-tyrosine kinase inhibitors (TKi) combined with other NSCLC treatments, including radiotherapy, cytotoxic chemotherapies, targeted therapies, and emerging immunotherapies...
2018: International Journal of Biological Sciences
V Kozlov, I Karpov, S Kovalenko, V Shamanin
AIM: Classic activating mutations L858R and deletions in exon 19 (19del) in the gene for epidermal growth factor receptor (EGFR) are associated with sensitivity of the non-small cell lung cancer (NSCLC) to therapy with tyrosine kinase inhibitors (TKI). Insertions in EGFR exon 19 (19ins) are rare mutations in NSCLC; response of cases with 19ins to TKI is not well studied. Here we report a case of NSCLC with 19ins in a Russian patient who was treated with gefitinib. We also overview cases of 19ins reported in the literature...
July 2017: Experimental Oncology
Nicolas Floc'h, Matthew J Martin, Jonathan W Riess, Jonathan P Orme, Anna D Staniszewska, Ludovic Menard, Maria Emanuela Cuomo, Daniel J O'Neill, Richard A Ward, M Raymond V Finlay, Darren McKerrecher, Mingshan Cheng, Daniel P Vang, Rebekah A Tsai, James G Keck, David R Gandara, Philip C Mack, Darren Ae Cross
EGFR exon 20 insertions (Ex20Ins) account for 4-10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to 1st and 2nd generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed...
February 26, 2018: Molecular Cancer Therapeutics
Akira Makino, Anna Miyazaki, Ayaka Tomoike, Hiroyuki Kimura, Kenji Arimitsu, Masahiko Hirata, Yoshiro Ohmomo, Ryuichi Nishii, Hidehiko Okazawa, Yasushi Kiyono, Masahiro Ono, Hideo Saji
Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR-TKIs) are used as molecular targeted therapy for non-small cell lung cancer (NSCLC) patients. The therapy is applied to the patients having EGFR-primary L858R mutation, but drug tolerance caused by EGFR-secondary mutation is occurred within one and half years. For the non-invasive detection of the EGFR-TKIs treatment positive patients by positron emission tomograpy (PET) imagaing, fluorine-18 labeled thienopyrimidine derivative, [18 F]FTP2 was newly synthesized...
February 8, 2018: Bioorganic & Medicinal Chemistry
Sun Min Lim, Nicholas L Syn, Byoung Chul Cho, Ross A Soo
The tyrosine kinase inhibitors (TKIs) directed at sensitizing mutations in the epidermal growth factor receptor (EGFR) gene represents a critical pillar in non-small cell lung cancer treatment. Despite the excellent disease control with initial EGFR TKI therapy, acquired resistance is ubiquitous and remains a key challenge. Investigations into the mechanisms which foster resistance to EGFR TKIs has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations...
February 20, 2018: Cancer Treatment Reviews
Ting-Hui Wu, Emily Han-Chung Hsiue, Jih-Hsiang Lee, Chia-Chi Lin, Wei-Yu Liao, Chao-Chi Ho, Jin-Yuan Shih, Chong-Jen Yu, James Chih-Hsin Yang
INTRODUCTION: The association between the response to first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and survival in EGFR mutation-positive non-small-cell lung cancer (NSCLC) remains unclear. We studied the association between the response to first-line EGFR-TKIs and survival using Response Evaluation Criteria In Solid Tumors (RECIST) and maximal tumor shrinkage. MATERIALS AND METHODS: We analyzed data from patients with advanced EGFR mutation-positive NSCLC enrolled in first-line gefitinib and afatinib trials...
February 1, 2018: Clinical Lung Cancer
D Westover, J Zugazagoitia, B C Cho, C M Lovly, L Paz-Ares
Patients with non-small-cell lung cancer (NSCLC) whose tumours harbour activating mutations within the epidermal growth factor receptor (EGFR) frequently derive significant clinical and radiographic benefits from treatment with EGFR tyrosine kinase inhibitors (TKIs). As such, prospective identification of EGFR mutations is now the standard of care worldwide. However, acquired therapeutic resistance to these agents invariably develops. Over the past 10 years, great strides have been made in defining the molecular mechanisms of EGFR TKI resistance in an effort to design rational strategies to overcome this acquired drug resistance...
January 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
W-H Hsu, J C-H Yang, T S Mok, H H Loong
Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs...
January 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Chee-Seng Tan, Nesaretnam Barr Kumarakulasinghe, Yi-Qing Huang, Yvonne Li En Ang, Joan Rou-En Choo, Boon-Cher Goh, Ross A Soo
Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development...
February 19, 2018: Molecular Cancer
Shang-Gin Wu, Jin-Yuan Shih
Recent advances in diagnosis and treatment are enabling a more targeted approach to treating lung cancers. Therapy targeting the specific oncogenic driver mutation could inhibit tumor progression and provide a favorable prognosis in clinical practice. Activating mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are a favorable predictive factor for EGFR tyrosine kinase inhibitors (TKIs) treatment. For lung cancer patients with EGFR-exon 19 deletions or an exon 21 Leu858Arg mutation, the standard first-line treatment is first-generation (gefitinib, erlotinib), or second-generation (afatinib) TKIs...
February 19, 2018: Molecular Cancer
Chi-Lu Chiang, Lei-Chi Wang, Hsiang-Ling Ho, Chun-Ming Tsai, Yi-Chen Yeh, Wen-Hu Hsu, Teh-Ying Chou, Chao-Hua Chiu, Yu-Chung Wu
Background: Occasionally, malignant pleural disease is only detected unexpectedly during surgery in patients with pulmonary adenocarcinoma. Previous studies mostly focused on the role of main tumor resection on patient's outcome, barely addressing the position of postoperative systemic therapy. Methods: The medical records of 5321 non-small cell lung cancer patients who underwent thoracic surgery between January 1990 and December 2012 were reviewed. Pulmonary adenocarcinoma patients with unexpected pleural spread noted during surgery were included...
January 12, 2018: Oncotarget
Jai-Nien Tung, Po-Lin Lin, Yao-Chen Wang, De-Wei Wu, Chi-Yi Chen, Huei Lee
Programmed death ligand (PD-L1) expression was associated with tumor immune escape and subsequent poor prognosis in non-small cell lung cancer (NSCLC). This expression was higher in patients with EGFR-mutated NSCLC tumors than in those with EGFR-wild-type (WT) NSCLC tumors. We therefore hypothesized that poor prognosis mediated by higher PD-L1 may be partially through conferring resistance to tyrosine kinase inhibitor (TKI) in NSCLC regardless of EGFR mutation. The change in PD-L1 expression following gene manipulation corresponded with changes in expression of HIF-1α and YAP1...
January 12, 2018: Oncotarget
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