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TKIs in ALK+ NSCLC

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https://www.readbyqxmd.com/read/28228224/-clinical-advanced-in-early-stage-alk-positive-non-small-cell-lung-cancer-patients
#1
Qiongqiong Gao, Xiangli Jiang, Chun Huang
Lung cancer is the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, with the majority of the cases diagnosed at the advanced stage. Molecular targeted therapy is becoming the focus attention for advanced NSCLC. Echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene (EML4-ALK) is among the most common molecular targets of NSCLC; its specific small-molecule tyrosine kinase inhibitors (TKIs) are approved for use in advanced NSCLC cases of ALK-positive...
February 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28185914/therapeutic-strategies-and-mechanisms-of-drug-resistance-in-anaplastic-lymphoma-kinase-alk-rearranged-lung-cancer
#2
REVIEW
Ryohei Katayama
Anaplastic lymphoma kinase (ALK) gene encoding the receptor tyrosine kinase ALK is expressed as a fusion gene in a variety of carcinomas. The expression of ALK is nearly undetectable in adults, and its activation is normally regulated by its ligands, FAM150A/B. However, ALK gene rearrangements result in different ALK fusion proteins that are constitutively expressed via the active promoter of fusion partner genes. ALK fusion proteins dimerize in a ligand-independent manner and lead to the dysregulation of cell proliferation via abnormal constitutive activation of ALK tyrosine kinase...
February 6, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28149754/non-small-cell-lung-cancer-nsclc-and-central-nervous-system-cns-metastases-role-of-tyrosine-kinase-inhibitors-tkis-and-evidence-in-favor-or-against-their-use-with-concurrent-cranial-radiotherapy
#3
REVIEW
Panagiota Economopoulou, Giannis Mountzios
Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM) represent a frequent complication of non-small cell lung cancer (NSCLC). Patients with BM comprise a heterogeneous group, with a median survival that ranges from 3 to 14 months. However, in the majority of patients, the occurrence of CNS metastases is usually accompanied by severe morbidity and substantial deterioration in quality of life. Local therapies, such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection, either alone or as part of a multimodality treatment are available treatment strategies for BM and the choice of therapy varies depending on patient group and prognosis...
December 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28149753/achievements-and-future-developments-of-alk-tkis-in-the-management-of-cns-metastases-from-alk-positive-nsclc
#4
REVIEW
Lorenza Landi, Federico Cappuzzo
Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements being one of the newest and most appealing. Presence of ALK fusions is associated with some particular clinical and pathological features, including a preferential seeding into the central nervous system (CNS). In addition, ALK rearrangements are recognized as the strongest predictor for benefit of anti-ALK therapy...
December 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28111120/real-world-eq5d-health-utility-scores-for-patients-with-metastatic-lung-cancer-by-molecular-alteration-and-response-to-therapy
#5
Catherine Labbé, Yvonne Leung, João Gabriel Silva Lemes, Erin Stewart, Catherine Brown, Andrea Perez Cosio, Mark Doherty, Grainne M O'Kane, Devalben Patel, Nicholas Cheng, Mindy Liang, Gursharan Gill, Alexandra Rett, Hiten Naik, Lawson Eng, Nicole Mittmann, Natasha B Leighl, Penelope A Bradbury, Frances A Shepherd, Wei Xu, Geoffrey Liu, Doris Howell
INTRODUCTION: Economic analyses of upcoming treatments for lung cancer benefit from real-world health utility scores (HUSs) in an era of targeted therapy. METHODS: A longitudinal cohort study at Princess Margaret Cancer Centre evaluated 1571 EQ5D-3L-derived HUSs in 475 outpatients with metastatic lung cancer across various disease states. Patients with epidermal growth factor receptor (EGFR) (n = 183) and anaplastic lymphoma kinase (ALK) (n = 38) driver alterations were enriched through targeted enrolment; patients with wild-type non-small-cell lung cancer (WT NSCLC) (n = 224) and small-cell lung cancer (SCLC) (n = 30) were sampled randomly...
December 28, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28007627/clinical-outcome-of-alk-positive-non-small-cell-lung-cancer-nsclc-patients-with-de-novo-egfr-or-kras-co-mutations-receiving-tyrosine-kinase-inhibitors-tkis
#6
Sabine Schmid, Oliver Gautschi, Sacha Rothschild, Michael Mark, Patrizia Froesch, Dirk Klingbiel, Hermann Reichegger, Wolfram Jochum, Joachim Diebold, Martin Früh
INTRODUCTION: NSCLC with de novo anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and EGFR or KRAS mutations co-occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients are poorly understood. METHODS: Outcomes of patients with metastatic NSCLC de novo co-alterations of ALK/EGFR or ALK/KRAS detected by fluorescence in situ hybridization (ALK) and sequencing (EGFR/KRAS) from six Swiss centers were analyzed. RESULTS: A total of 14 patients with adenocarcinoma were identified...
December 19, 2016: Journal of Thoracic Oncology
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
#7
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
#8
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: Anaplastic lymphoma receptor tyrosine kinase gene (ALK) fusion is a distinct molecular subclassification of NSCLC that is targeted by anaplastic lymphoma kinase (ALK) inhibitors. We established a transgenic mouse model that expresses tumors highly resembling human NSCLC harboring echinoderm microtubule associated protein like 4 gene (EML)-ALK fusion. We aimed to test an EML4-ALK transgenic mouse model as a platform for assessing the efficacy of ALK inhibitors and examining mechanisms of acquired resistance to ALK inhibitors...
March 2017: 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
#9
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
#10
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
#11
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...
November 15, 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
#12
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 EGFR pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) 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...
January 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27623999/novel-immunotherapy-in-the-treatment-of-advanced-non-small-cell-lung-cancer
#13
G Santabarbara, P Maione, A Rossi, G Palazzolo, C Gridelli
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. The cancer cells use mechanisms able to avoid the immune control has led to the development of drugs able to overcome this escape route...
December 2016: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/27573755/the-role-of-the-alk-receptor-in-cancer-biology
#14
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
#15
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
#16
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...
October 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27515517/the-role-of-micrornas-in-resistance-to-targeted-treatments-of-non-small-cell-lung-cancer
#17
REVIEW
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
#18
Ramon Andrade de Mello, Davi J J Liu, Pedro N Aguiar, Hakaru Tadokoro
BACKGROUND: 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...
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
#19
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...
July 22, 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
#20
Francesco Facchinetti, Yohann Loriot, Mei-Shiue Kuo, Linda Mahjoubi, Ludovic Lacroix, David Planchard, Benjamin Besse, Françoise Farace, Nathalie Auger, Jordi Remon, Jean-Yves Scoazec, Fabrice André, Jean-Charles Soria, Luc Friboulet
BACKGROUND: The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to 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. METHODS: A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib...
December 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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