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TKIs in ALK+ NSCLC

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https://www.readbyqxmd.com/read/27879019/screening-for-alk-abnormalities-in-central-nervous-system-metastases-of-non-small-cell-lung-cancer-alk-abnormalities-in-cns-metastases-of-nsclc
#1
Marcin Nicoś, Bożena Jarosz, Paweł Krawczyk, Kamila Wojas-Krawczyk, Tomasz Kucharczyk, Marek Sawicki, Juliusz Pankowski, Tomasz Trojanowski, Janusz Milanowski
Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. However, there are no reports concerning the frequency of ALK rearrangement in CNS metastases...
November 23, 2016: Brain Pathology
https://www.readbyqxmd.com/read/27836576/establishment-of-a-conditional-transgenic-mouse-model-recapitulating-eml4-alk-positive-human-non-small-cell-lung-cancer
#2
Kyoung Ho Pyo, Sun Min Lim, Hye Ryun Kim, Young Hoon Sung, Mi Ran Yun, Sung-Moo Kim, Hwan Kim, Han Na Kang, Ji Min Lee, Sang Gyun Kim, Chae Won Park, Hyun Chang, Hyo Sup Shim, Han-Woong Lee, Byoung Chul Cho
BACKGROUND: ALK fusion is a distinct molecular subclassification of non-small-cell lung cancer (NSCLC) that is targeted by ALK inhibitors. We established a transgenic mouse model that expresses tumors highly resembling human NSCLC harboring EML-ALK fusion. We aimed to test EML4-ALK transgenic mouse model as a platform for assessing efficacy of ALK inhibitor and examining mechanisms of acquired resistance to ALK inhibitor. MATERIALS AND METHODS: Transgenic mouse lines harboring LoxP-STOP-LoxP- FLAG tagged human EML4-ALK (variant 1) transgene was established using C57BL/6N mice...
November 8, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27821131/frequency-of-egfr-t790m-mutation-and-multimutational-profiles-of-rebiopsy-samples-from-non-small-cell-lung-cancer-developing-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-in-japanese-patients
#3
Ryo Ko, Hirotsugu Kenmotsu, Masakuni Serizawa, Yasuhiro Koh, Kazushige Wakuda, Akira Ono, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Mitsuhiro Isaka, Masahiro Endo, Takashi Nakajima, Yasuhisa Ohde, Nobuyuki Yamamoto, Kazuhisa Takahashi, Toshiaki Takahashi
BACKGROUND: The majority of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Minimal information exists regarding genetic alterations in rebiopsy samples from Asian NSCLC patients who develop acquired resistance to EGFR-TKIs. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who had undergone rebiopsies after developing acquired resistance to EGFR-TKIs...
November 8, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27799783/personalized-treatment-in-advanced-alk-positive-non-small-cell-lung-cancer-from-bench-to-clinical-practice
#4
REVIEW
Antonio Passaro, Chiara Lazzari, Niki Karachaliou, Gianluca Spitaleri, Alessia Pochesci, Chiara Catania, Rafael Rosell, Filippo de Marinis
The discovery of anaplastic lymphoma kinase (ALK) gene rearrangements and the development of tyrosine kinase inhibitors (TKI) that target them have achieved unprecedented success in the management of patients with ALK-positive non-small cell lung cancer (NSCLC). Despite the high efficacy of crizotinib, the first oral ALK TKI approved for the treatment of ALK-positive NSCLC, almost all patients inevitably develop acquired resistance, showing disease progression in the brain or in other parenchymal sites. Second- or third-generation ALK TKIs have shown to be active in crizotinib-pretreated or crizotinib-naïve ALK-positive patients, even in those with brain metastases...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27780853/the-potent-alk-inhibitor-brigatinib-ap26113-overcomes-mechanisms-of-resistance-to-first-and-second-generation-alk-inhibitors-in-preclinical-models
#5
Sen Zhang, Rana Anjum, Rachel Squillace, Sara Nadworny, Tianjun Zhou, Jeff Keats, Yaoyu Ning, Scott D Wardwell, David Miller, Youngchul Song, Lindsey Eichinger, Lauren Moran, Wei-Sheng Huang, Shuangying Liu, Dong Zou, Yihan Wang, Qurish Mohemmad, Hyun Gyung Jang, Emily Ye, Narayana Narasimhan, Frank Wang, Juan Miret, Xiaotian Zhu, Tim Clackson, David Dalgarno, William C Shakespeare, Victor M Rivera
PURPOSE: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK(+)) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27707887/overcoming-egfr-bypass-signal-induced-acquired-resistance-to-alk-tyrosine-kinase-inhibitors-in-alk-translocated-lung-cancer
#6
Masayoshi Miyawaki, Hiroyuki Yasuda, Tetsuo Tani, Junko Hamamoto, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Shigenari Nukaga, Toshiyuki Hirano, Ichiro Kawada, Katsuhiko Naoki, Yuichiro Hayashi, Tomoko Betsuyaku, Kenzo Soejima
: Activation of the epidermal growth factor receptor (EGFR) pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLCs) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALK-TKIs...
October 5, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27623999/novel-immunotherapy-in-the-treatment-of-advanced-non-small-cell-lung-cancer
#7
G Santabarbara, P Maione, A Rossi, G Palazzolo, C Gridelli
INTRODUCTION: Lung cancers remain the principal cause of death cancer-related worldwide with a poor survival rate at five years from diagnosis. In patients with NSCLC harboring specific genetic alterations the anti EGFR TKIs and the ALK TKIs have improved the response rate and the quality of life compared to standard platinum-based chemotherapy. New approaches possibly applicable at the major of patients are needed. AREAS COVERED: The discovery that the immune system plays a fundamental role in the fight against cancer...
September 23, 2016: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/27573755/the-role-of-the-alk-receptor-in-cancer-biology
#8
REVIEW
B Hallberg, R H Palmer
A vast array of oncogenic variants has been identified for anaplastic lymphoma kinase (ALK). Therefore, there is a need to better understand the role of ALK in cancer biology in order to optimise treatment strategies. This review summarises the latest research on the receptor tyrosine kinase ALK, and how this information can guide the management of patients with cancer that is ALK-positive. A variety of ALK gene alterations have been described across a range of tumour types, including point mutations, deletions and rearrangements...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27544060/clinical-activity-of-alectinib-in-advanced-ret-rearranged-non-small-cell-lung-cancer
#9
Jessica J Lin, Elizabeth Kennedy, Lecia V Sequist, Priscilla K Brastianos, Kelly E Goodwin, Sara Stevens, Alexandra C Wanat, Lisa L Stober, Subba R Digumarthy, Jeffrey A Engelman, Alice T Shaw, Justin F Gainor
INTRODUCTION: Chromosomal rearrangements involving rearranged during transfection gene (RET) occur in 1% to 2% of NSCLCs and may confer sensitivity to rearranged during transfection (RET) inhibitors. Alectinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor (TKI) that also has anti-RET activity in vitro. The clinical activity of alectinib in patients with RET-rearranged NSCLC has not yet been reported. METHODS: We have described four patients with advanced RET-rearranged NSCLC who were treated with alectinib (600 mg twice daily [n = 3] or 900 mg twice daily [n = 1]) as part of single-patient compassionate use protocols or off-label use of the commercially available drug...
August 17, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27533086/clinical-outcomes-of-advanced-non-small-cell-lung-cancer-patients-with-egfr-mutation-alk-rearrangement-and-egfr-alk-co-alterations
#10
Na-Na Lou, Xu-Chao Zhang, Hua-Jun Chen, Qing Zhou, Li-Xu Yan, Zhi Xie, Jian Su, Zhi-Hong Chen, Hai-Yan Tu, Hong-Hong Yan, Zhen Wang, Chong-Rui Xu, Ben-Yuan Jiang, Bin-Chao Wang, Xiao-Yan Bai, Wen-Zhao Zhong, Yi-Long Wu, Jin-Ji Yang
The co-occurrence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular subtype of non-small-cell lung cancer (NSCLC). Herein, we assessed the clinical outcomes and incidence of acquired resistance to tyrosine kinase inhibitors (TKIs) in this subtype. So we enrolled 118 advanced NSCLC treated with TKIs. EGFR mutations and ALK rearrangements were detected by DNA sequencing or Scorpion amplification refractory mutation system and fluorescence in situ hybridization respectively...
August 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27515517/the-role-of-micrornas-in-resistance-to-targeted-treatments-of-non-small-cell-lung-cancer
#11
Hongjing Zang, Weiyuan Wang, Songqing Fan
PURPOSE: Non-small cell lung cancer (NSCLC), accounting for the most of lung cancers, is usually diagnosed in advanced stage. Targeted treatments boost advanced NSCLC patients with certain mutations, but early drug resistance blocks the advantages of target medicine. MicroRNAs (miRNAs) are regarded as a cluster of small noncoding and posttranscriptionally negative regulating RNAs. We want to explore the role of miRNAs in resistance to targeted treatments of NSCLC to improve the prognosis...
August 11, 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27491402/egfr-and-eml4-alk-updated-therapies-in-non-small-cell-lung-cancer
#12
Ramon Andrade Bezerra De Mello, Davi Jing Jue Liu, Pedro N Aguiar, Hakaru Tadokoro
: Non-small cell lung cancer is the leading cancer-related cause of death. OBJECTIVE: We review the latest therapies for NSCLC with EGFR and ELM4-ALK mutations as well as the most relevant studies and promising patents. METHOD: A literature search of PubMed database was carried out to identify recent Clinical Trials using EGFR therapies and novel patents involving diagnosis and therapies on NSCLC. We conducted a search to find new therapy strategies, new biomarkers, and selected five patents we find relevant...
August 2, 2016: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/27455248/non-invasive-methods-to-monitor-mechanisms-of-resistance-to-tyrosine-kinase-inhibitors-in-non-small-cell-lung-cancer-where-do-we-stand
#13
REVIEW
Paola Ulivi
The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific drugs are have been developed. However, other molecular alterations have also been reported as induced resistance mechanisms to EGFR-TKIs. Similarly, there is growing evidence of acquired resistance mechanisms to anaplastic lymphoma kinase (ALK)-TKI treatment...
2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27401242/crizotinib-resistant-ros1-mutations-reveal-a-predictive-kinase-inhibitor-sensitivity-model-for-ros1-and-alk-rearranged-lung-cancers
#14
Francesco Facchinetti, Yohann Loriot, Mei-Shiue Cassin-Kuo, Linda Mahjoubi, Ludovic Lacroix, David Planchard, Benjamin Besse, Nathalie Auger, Françoise Farace, Jordi Remon, Jean-Yves Scoazec, Fabrice Andre, Jean-Charles Soria, Luc Friboulet
BACKGROUND: The identification of molecular mechanisms conferring resistance to Tyrosine Kinase Inhibitor (TKIs) is a key-step to improve therapeutic results for patients with oncogene-addiction. Several alterations leading to Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far...
July 11, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27318655/progression-free-and-overall-survival-of-patients-with-alk-rearrangement-positive-non-small-cell-lung-cancer-treated-sequentially-with-crizotinib-and-alectinib
#15
Satomi Watanabe, Hidetoshi Hayashi, Kunio Okamoto, Kimiko Fujiwara, Yoshikazu Hasegawa, Hiroyasu Kaneda, Kaoru Tanaka, Masayuki Takeda, Kazuhiko Nakagawa
INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first- and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC...
May 18, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/27285610/exosomal-mirna-analysis-in-non-small-cell-lung-cancer-nsclc-patients-plasma-through-qpcr-a-feasible-liquid-biopsy-tool
#16
Marco Giallombardo, Jorge Chacártegui Borrás, Marta Castiglia, Nele Van Der Steen, Inge Mertens, Patrick Pauwels, Marc Peeters, Christian Rolfo
The discovery of alterations in the EGFR and ALK genes, amongst others, in NSCLC has driven the development of targeted-drug therapy using selective tyrosine kinase inhibitors (TKIs). To optimize the use of these TKIs, the discovery of new biomarkers for early detection and disease progression is mandatory. These plasma-isolated exosomes can be used as a non-invasive and repeatable way for the detection and follow-up of these biomarkers. One ml of plasma from 12 NSCLC patients, with different mutations and treatments (and 6 healthy donors as controls), were used as exosome sources...
2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27239236/overcoming-resistance-to-first-second-generation-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-and-alk-inhibitors-in-oncogene-addicted-advanced-non-small-cell-lung-cancer
#17
REVIEW
Ourania Romanidou, Lorenza Landi, Federico Cappuzzo, Raffaele Califano
Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10-12 months of treatment...
May 2016: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/27220787/-combined-therapy-with-targeted-drugs-in-lung-cancer
#18
Seiji Yano
As targeted therapies for lung cancer, EGFR tyrosine kinase inhibitors(EGFR-TKIs)and ALK-TKIs have been approved for EGFR mutation-positive advanced non-small cell lung cancer(NSCLC)and ALK-fusion gene-positive advanced NSCLC, respectively. Very recently, an anti-immune checkpoint antibody was approved for advanced or recurrent NSCLC. In this article, the current status of combined therapy is reviewed with a focus on EGFR-TKIs, which are the most frequently used targeted therapies in clinical practice for lung cancer...
April 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/27178681/asco-plenary-sessions-impact-legacy-future
#19
REVIEW
Andrae Vandross, Vinay Prasad, Sham Mailankody
The ASCO annual meeting draws a large crowd of physicians, cancer researchers, policy makers, and industry representatives. The crown jewel of the annual events is the Plenary session where impactful, influential and visible abstracts are selected for the largest audience. Plenary topics are frequently paired with concurrent New England Journal or Lancet publications.  Here, we review 9 years of ASCO plenary sessions.  Several themes emerge.  First, many of the topics selected have indeed been practice changing, such as the use of ALK inhibitors for ALK rearranged NSCLC, or checkpoint inhibitors in metastatic melanoma...
June 2016: Seminars in Oncology
https://www.readbyqxmd.com/read/27141355/upregulation-of-pd-l1-by-eml4-alk-fusion-protein-mediates-the-immune-escape-in-alk-positive-nsclc-implication-for-optional-anti-pd-1-pd-l1-immune-therapy-for-alk-tkis-sensitive-and-resistant-nsclc-patients
#20
Shaodong Hong, Nan Chen, Wenfeng Fang, Jianhua Zhan, Qing Liu, Shiyang Kang, Xiaobo He, Lin Liu, Ting Zhou, Jiaxing Huang, Ying Chen, Tao Qin, Yaxiong Zhang, Yuxiang Ma, Yunpeng Yang, Yuanyuan Zhao, Yan Huang, Li Zhang
Driver mutations were reported to upregulate programmed death-ligand 1 (PD-L1) expression. However, how PD-L1 expression and immune function was affected by ALK-TKIs and anti-PD-1/PD-L1 treatment in ALK positive non-small-cell lung cancer (NSCLC) remains poorly understood. In the present study, western-blot, real-time PCR, flow cytometry and immunofluorescence were employed to explore how PD-L1 was regulated by ALK fusion protein. ALK-TKIs and relevant inhibitors were used to identify the downstream signaling pathways involved in PD-L1 regulation...
March 2016: Oncoimmunology
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