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Egfr-tki resistance

Xin Li, Han Qi, Gou Qing, Ze Song, Lin Xie, Fei Cao, Xiaoming Chen, Weijun Fan
BACKGROUND: Although patients with EGFR-mutant non-small-cell lung cancer (NSCLC) benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs), outcomes are limited by the eventual development of acquired resistance. We conducted a retrospective study to evaluate the efficacy and feasibility of EGFR-TKI therapy beyond focal progression, associated with microwave ablation. METHODS: Patients with metastatic EGFR-mutant NSCLC treated with EGFR-TKIs at our institutions from May 2012 to December 2017 were identified...
June 20, 2018: Thoracic Cancer
Keigo Kobayashi, Katsuhiko Naoki, Tadashi Manabe, Keita Masuzawa, Hanako Hasegawa, Hiroyuki Yasuda, Ichiro Kawada, Kenzo Soejima, Tomoko Betsuyaku
Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor, exerts remarkable effects against EGFR T790M resistance mutation-positive non-small cell lung cancer. Identifying T790M mutation by re-biopsy is essential before prescribing osimertinib. Tissue biopsy is the golden standard for this purpose, but several factors limit its success rate. The liquid biopsy with blood, using circulating tumor DNA, has been an alternative method. However, the true biological meaning and equivalence of liquid biopsy and tumor biopsy are still under investigation...
2018: OncoTargets and Therapy
G M O'Kane, T A Barnes, N B Leighl
Tumours with sensitizing mutations in the EGFR gene constitute a distinct molecular subgroup of non-small-cell lung cancers (nsclcs) that benefit from precision medicine. First- and second-generation epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as upfront therapy for EGFR -mutated advanced nsclc and, compared with chemotherapy, have resulted in superior progression-free survival, improved tumour response rates, and improved quality of life. However, resistance inevitably develops, and the third-generation tki osimertinib has been approved to target the gatekeeper EGFR mutation T790M, which is responsible for resistance in 60% of cases...
June 2018: Current Oncology
S Morin-Ben Abdallah, V Hirsh
Despite recent advances in the systemic therapy of non-small-cell lung cancer (nsclc), the prognosis for stage iv disease remains poor. The discovery of targetable mutations has led to new treatment options. The most common mutations, the EGFR activating mutations, are present in about 50% of Asian patients and up to 15% of white patients. First-generation reversible epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) have led to improved survival in patients positive for EGFR activating mutations, but resistance eventually leads to disease progression...
June 2018: Current Oncology
Xuanzong Li, Shijiang Wang, Butuo Li, Zhen Wang, Shuheng Shang, Yang Shao, Xindong Sun, Linlin Wang
The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has shown significant clinical efficacy against the EGFR T790M mutation in non-small cell lung cancer (NSCLC) patients. However, resistance inevitably occurs, and the mechanisms leading to treatment failure need to be further investigated. The B-cell lymphoma 2 (BCL-2)-like 11 (BIM) deletion polymorphism, which occurs at a frequency of 21% in East Asians but is absent in African and European populations, has been associated with resistance to first-generation EGFR TKIs, such as gefitinib and erlotinib; and is a poor prognostic factor for NSCLC patients with EGFR mutations...
June 16, 2018: Targeted Oncology
Chang Liu, Tatiana Shaurova, Suzanne Shoemaker, Martin Petkovich, Pamela A Hershberger, Yun Wu
Mutation in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene drives the development of lung cancer. EGFR tyrosine kinase inhibitors (EGFR TKI) including erlotinib and afatinib are initially effective in treating EGFR mutant non-small cell lung cancer (NSCLC). However, drug resistance quickly develops due to several mechanisms, including induction of the epithelial-mesenchymal transition (EMT). No effective therapies are currently available for patients who develop EMT-associated EGFR TKI resistance...
June 14, 2018: Molecular Pharmaceutics
Jan Nyrop Jakobsen, Eric Santoni-Rugiu, Morten Grauslund, Linea Melchior, Jens Benn Sørensen
Background: Patients with EGFR -mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes. Methods: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR -mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET -amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR -mutated tumor samples from erlotinib-treated patients...
May 25, 2018: Oncotarget
Shingo Sakashita, Aya Shiba-Ishii, Yoshihiko Murata, Ryutaro Sekimoto, Yuko Minami, Yukio Sato, Masayuki Noguchi
EGFR T790M mutation is a crucial gene alteration causing EGFR TKI resistance. However, the implication of T790M mutation is still unknown for the stepwise progression of EGFR TKI naïve lung adenocarcinoma. In this study, we studied site-related EGFR T790M mutation analysis in EGFR TKI naïve lung adenocarcinomas harboring double EGFR mutation (L858R and T790M or Exon 19 deletion (Del.19) and T790M) by droplet digital (dd) PCR method. We examined three resected lung adenocarcinoma cases harboring EGFR double mutation including T790M...
May 21, 2018: Pathology, Research and Practice
Alexa B Schrock, Viola W Zhu, Wen-Son Hsieh, Russell Madison, Benjamin Creelan, Jeffrey Silberberg, Dan Costin, Anjali Bharne, Ioana Bonta, Thangavijayan Bosemani, Petros Nikolinakos, Jeffrey S Ross, Vincent A Miller, Siraj M Ali, Samuel J Klempner, Sai-Hong Ignatius Ou
INTRODUCTION: We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR TKIs. METHODS: EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (FFPE tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians...
June 5, 2018: Journal of Thoracic Oncology
Junji Uchino, Akira Nakao, Nobuyo Tamiya, Yoshiko Kaneko, Tadaaki Yamada, Kenichi Yoshimura, Masaki Fujita, Koichi Takayama
BACKGROUND: Advances in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment led to research on the mechanism of the resistance have revealed that an occurrence of T790M gene mutation generated in exon 20 of the EGFR gene is associated with approximately 50% to 60% of observed resistance. Osimertinib, a 3rd-generation EGFR-TKI, has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. In this study, we prospectively investigate the efficacy and safety of osimertinib in elderly patients aged ≥75 years, with ineffective prior EGFR-TKI treatment or with recurrence of EGFR-TKI mutation-positive or T790M mutation-positive nonsmall-cell lung cancer...
June 2018: Medicine (Baltimore)
Arenda D Meedendorp, Arja Ter Elst, Nils A 't Hart, Harry J M Groen, Ed Schuuring, Anthonie J van der Wekken
A 62-year-old man was referred to our university hospital for treatment of advanced adenocarcinoma of the lung after disease progression on two lines of EGFR TKI and one line of chemotherapy. Fluorescent in situ hybridization analysis upon progression showed an HER2 amplification. At our weekly Molecular Tumor Board (MTB), a decision was made to treat this patient with afatinib, which resulted in a partial response. However, progression was observed with a facial nerve paresis due to a metastasis in the skull...
2018: Frontiers in Oncology
Hanh-Nguyen Thi Vu, Dat Tien Nguyen, Huy Quang Nguyen, Ha Hoang Chu, Son Ky Chu, Minh Van Chau, Quyet-Tien Phi
The endophytic actinomycete strain YBQ59 was isolated from Cinnamomum cassia Prels in Yen Bai province (21°53'14″N; 104°35'9″E) of northern Vietnam. Based on analysis of morphological, physiological characteristics and 16S rRNA gene sequence (GenBank Acc. No. MF950891), the strain YBQ59 possessed high similarity to Streptomyces cavourensis subsp. cavourensis strain NRRL 2740, therefore assigned as S. cavourensis YBQ59. The ethyl acetate extract of the YBQ59 culture broth isolated eight pure secondary metabolites, identified as 1-monolinolein (1), bafilomycin D (2), nonactic acid (3), daidzein (4), 3'-hydroxydaidzein (5), 5,11-epoxy-10-cadinanol (6), prelactone B (7), and daucosterol (8)...
June 4, 2018: Current Microbiology
Hideyuki Niwa, Yoshiro Nakahara, Jiichiro Sasaki, Noriyuki Masuda
Most patients with non-small cell lung cancer with common epidermal growth factor receptor (EGFR) mutations respond dramatically to EGFR tyrosine kinase inhibitors (TKIs), but data are limited on the response of tumours with uncommon mutations. We present the case of a 68-year-old man with stage IV lung adenocarcinoma with an uncommon EGFR mutation in exon 21 (L861Q). The disease progressed 2 years after he started erlotinib (150 mg daily). Using a transbronchial lung biopsy, we detected additional mutations in exon 20 (T790M) and exon 21 (L858R)...
June 4, 2018: BMJ Case Reports
Dimitrios C Ziogas, Anna Tsiara, Georgios Tsironis, Maria Lykka, Michalis Liontos, Aristotelis Bamias, Meletios-Athanasios Dimopoulos
Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients...
April 2018: Annals of Translational Medicine
Giannis Mountzios
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represent the standard of care for advanced non-small cell lung cancer (NSCLC) patients whose tumours harbor an activating EGFR mutation. Unfortunately, resistance to first- and second-generation EGFR-TKIs inevitably occurs in all patients with EGFR-mutant disease approximately within a year of treatment. At least half of these cases are attributed to the emergence of a secondary mutation in exon 20 of the EGFR gene, namely the T790M mutation...
April 2018: Annals of Translational Medicine
Duc-Hiep Bach, Donghwa Kim, Song Yi Bae, Won Kyung Kim, Ji-Young Hong, Hye-Jung Lee, Nirmal Rajasekaran, Soonbum Kwon, Yanhua Fan, Thi-Thu-Trang Luu, Young Kee Shin, Jeeyeon Lee, Sang Kook Lee
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used clinically as target therapies for lung cancer patients, but the occurrence of acquired drug resistance limits their efficacy. Nicotinamide N-methyltransferase (NNMT), a cancer-associated metabolic enzyme, is commonly overexpressed in various human tumors. Emerging evidence also suggests a crucial loss of function of microRNAs (miRNAs) in modulating tumor progression in response to standard therapies. However, their precise roles in regulating the development of drug-resistant tumorigenesis are still poorly understood...
June 1, 2018: Molecular Therapy. Nucleic Acids
Shuyan Meng, Guorui Wang, Yang Lu, Zhen Fan
OBJECTIVE: Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are important transcription factors regulating expression of genes involved in cell survival. HIF-1α and c-Jun are key components of HIF-1 and AP-1, respectively, and are regulated by epidermal growth factor receptor (EGFR)-mediated cell signaling and tumor microenvironmental cues. The roles of HIF-1α and c-Jun in development of resistance to EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) with activating mutation of EGFR have not been explored...
July 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Keke Nie, Zhongfa Zhang, Chunling Zhang, Chuanxin Geng, Ling Zhang, Xiajuan Xu, Shichao Liu, Songping Wang, Xingjun Zhuang, Ketao Lan, Youxin Ji
OBJECTIVE: To compare the efficacy and toxicity of osimertinib versus docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated NSCLC. METHODS: In this phase 3, open-label, three-center study, we randomly assigned (1:1) previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients into two groups. These patients had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum...
July 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Jin Woo Joo, Min Hee Hong, Hyo Sup Shim
OBJECTIVES: We aimed to investigate the clinical characteristics of lung adenocarcinomas with acquired EGFR T790M mutation focusing on brain metastasis and survival. MATERIALS AND METHODS: Our study included patients who had lung adenocarcinoma harboring EGFR mutation at 1st biopsy and then underwent 2nd biopsy after resistance to first- or second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Statistical analyses were performed to examine the associations between clinicopathologic features of lung adenocarcinoma and presence of acquired T790M mutation...
July 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Minglei Yang, Xiaoling Tong, Xiang Xu, Enkuo Zheng, Junjun Ni, Junfang Li, Junrong Yan, Yang W Shao, Guofang Zhao
Missense mutations in EGFR exon 20 are rare in non-small-cell lung cancer (NSCLC), and mostly insensitive to the first generation tyrosine kinase inhibitors (TKIs) of EGFR. However, their responses to the third generation TKI are unclear. Here, we reported a patient with advanced NSCLC harboring a rare EGFR H773L/V774M mutation complex. Although he was irresponsive to the first generation TKI gefitinib, he demonstrated sustained disease control to osimertinib, suggesting that this complex is an activating mutation of EGFR and can be suppressed by osimertinib...
July 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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