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Tyrosine kinase inhibitors

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https://www.readbyqxmd.com/read/28431398/decreased-calpain-activity-in-chronic-myeloid-leukemia-impairs-apoptosis-by-increasing-survivin-in-myeloid-progenitors-and-xiap1-in-differentiating-granulocytes
#1
Weiqi Huang, Ling Bei, Elizabeth E Hjort, Elizabeth A Eklund
Chronic Myeloid Leukemia (CML) is characterized by translocations between chromosomes 9 and 22, resulting in expression of Bcr-abl oncogenes. Although the clinical course of CML was revolutionized by development of Bcr-abl-directed tyrosine kinase inhibitors (TKIs), CML is not cured by these agents. Specifically, the majority of subjects relapsed in clinical trials attempting TKI discontinuation, suggesting persistence of leukemia stem cells (LSCs) even in molecular remission. Identifying mechanisms of CML-LSC persistence may suggest rationale therapeutic targets to augment TKI efficacy and lead to cure...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430774/is-nintedanib-effective-for-idiopathic-pulmonary-fibrosis
#2
Alejandro Jeldres, Gonzalo Labarca
Idiopathic pulmonary fibrosis has poor prognosis and effective therapies are scarce. In the search for treatments that can modify the course of the disease, nintedanib (BIBF 1120), a tyrosine kinase inhibitor, has emerged as an alternative. However, its role is still unclear. To answer this question, we searched in Epistemonikos database, which is maintained by screening multiple sources of information. We identified seven systematic reviews including seven randomized trials overall. We extracted data, conducted a meta-analysis and generated a summary of findings table using the GRADE approach...
April 10, 2017: Medwave
https://www.readbyqxmd.com/read/28430711/evaluation-of-kdr-rs34231037-as-a-predictor-of-sunitinib-efficacy-in-patients-with-metastatic-renal-cell-carcinoma
#3
María Apellániz-Ruiz, Meta H Diekstra, Juan M Roldán, Epie Boven, Daniel Castellano, Hans Gelderblom, Ron H J Mathijssen, Jesse J Swen, Stefan Böhringer, Jesús García-Donás, Brian I Rini, Henk-Jan Guchelaar, Cristina Rodríguez-Antona
The identification of biomarkers able to predict clinical benefit from vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors is urgently needed. Recently, Maitland and colleagues described an association between KDR-rs34231037 and soluble VEGFR2 levels as well as pazopanib pharmacodynamics. We investigated in a well-characterized series of metastatic clear cell renal cell carcinoma patients whether rs34231037 could influence sunitinib response. Clinical data and DNA were available from an international series of 276 patients...
April 20, 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28430623/clinical-efficacy-of-icotinib-in-lung-cancer-patients-with-different-egfr-mutation-status-a-meta-analysis
#4
REVIEW
Jian Qu, Ya-Nan Wang, Ping Xu, Da-Xiong Xiang, Rui Yang, Wei Wei, Qiang Qu
Icotinib is a novel and the third listed epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which exerts a good anti-tumor efficacy on non-small cell lung cancer (NSCLC). The efficacy of EGFR-TKIs has been shown to be associated with the EGFR mutation status, especially exon 19 deletion (19Del) and exon 21 L858R mutation. Therefore, a meta-analysis was performed to assess the efficacy of icotinib in NSCLC patients harboring EGFR mutations (19Del or L858R) and wild type (19Del and L858R loci wild type)...
February 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429795/cd200-positive-cancer-associated-fibroblasts-augment-the-sensitivity-of-epidermal-growth-factor-receptor-mutation-positive-lung-adenocarcinomas-to-egfr-tyrosine-kinase-inhibitors
#5
Masayuki Ishibashi, Shinya Neri, Hiroko Hashimoto, Tomoyuki Miyashita, Tatsuya Yoshida, Yuka Nakamura, Hibiki Udagawa, Keisuke Kirita, Shingo Matsumoto, Shigeki Umemura, Kiyotaka Yoh, Seiji Niho, Masahiro Tsuboi, Kenkichi Masutomi, Koichi Goto, Atsushi Ochiai, Genichiro Ishii
Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28428442/combination-of-ibrutinib-and-abt-199-in-diffuse-large-b-cell-lymphoma-and-follicular-lymphoma
#6
Hsu-Ping Kuo, Scott A Ezell, Karl J Schweighofer, Leo Wk Cheung, Sidney Hsieh, Mutiah Apatira, Mint Sirisawad, Karl Eckert, Ssucheng J Hsu, Chun-Te Chen, Darrin M Beaupre, Matthias Versele, Betty Y Chang
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance...
April 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28428148/plasma-ctdna-analysis-for-detection-of-the-egfr-t790m-mutation-in-patients-with-advanced-non-small-cell-lung-cancer
#7
Suzanne Jenkins, James C-H Yang, Suresh S Ramalingam, Karen Yu, Sabina Patel, Susie Weston, Rachel Hodge, Mireille Cantarini, Pasi A Jänne, Tetsuya Mitsudomi, Glenwood D Goss
INTRODUCTION: Tumor biopsies for detecting epidermal growth factor receptor mutations (EGFRm) in advanced non-small cell lung cancer (NSCLC) are invasive, costly and not always feasible for patients with late-stage disease. The clinical utility of the cobas(®) EGFR Mutation Test v2 with plasma samples from patients with NSCLC at disease progression following previous EGFR-tyrosine kinase inhibitor (TKI) therapy was investigated to determine osimertinib treatment eligibility. METHODS: Matched tumor tissue and plasma samples from patients screened for AURA extension and AURA2 phase II studies were tested for EGFRm using tissue- and plasma-based cobas(®) EGFR Mutation Tests v2...
April 17, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28427515/fgfr-a-promising-druggable-target-in-cancer-molecular-biology-and-new-drugs
#8
REVIEW
Rut Porta, Roberto Borea, Andreia Coelho, Shahanavaj Khan, António Araújo, Pablo Reclusa, Tindara Franchina, Nele Van Der Steen, Peter Van Dam, Jose Ferri, Rafael Sirera, Aung Naing, David Hong, Christian Rolfo
INTRODUCTION: The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. AREAS COVERED: This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies...
May 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28427247/molecular-testing-of-lung-cancers
#9
Hyo Sup Shim, Yoon-La Choi, Lucia Kim, Sunhee Chang, Wan-Seop Kim, Mee Sook Roh, Tae-Jung Kim, Seung Yeon Ha, Jin-Haeng Chung, Se Jin Jang, Geon Kook Lee
Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics...
April 21, 2017: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/28427238/clinical-features-and-treatment-outcome-of-non-small-cell-lung-cancer-nsclc-patients-with-uncommon-or-complex-epidermal-growth-factor-receptor-egfr-mutations
#10
Stefano Frega, Martina Lorenzi, Matteo Fassan, Stefano Indraccolo, Fiorella Calabrese, Adolfo Favaretto, Laura Bonanno, Valentina Polo, Giulia Zago, Francesca Lunardi, Ilaria Attili, Alberto Pavan, Massimo Rugge, Valentina Guarneri, PierFranco Conte, Giulia Pasello
INTRODUCTION: Tyrosine-kinase inhibitors (TKIs) represent the best treatment for advanced non-small cell lung cancer (NSCLC) with common exon 19 deletion or exon 21 epidermal growth factor receptor mutation (EGFRm). This is an observational study investigating epidemiology, clinical features and treatment outcome of NSCLC cases harbouring rare/complex EGFRm. RESULTS: Among 764 non-squamous NSCLC cases with known EGFRm status, 26(3.4%) harboured rare/complex EGFRm...
March 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427161/efficacy-of-epidermal-growth-factor-receptor-egfr-tyrosine-kinase-inhibitors-tkis-in-targeted-therapy-of-lung-squamous-cell-carcinoma-patients-with-egfr-mutation-a-pooled-analysis
#11
Jingqi Zhuang, Yongfeng Yu, Ziming Li, Shun Lu
PURPOSE: This pooled analysis aims to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in lung squamous cell carcinoma with EGFR mutation. METHODS: Advanced stage (IIIB/IV) lung squamous cell carcinoma patients with EGFR mutations treated with EGFR-TKIs were extracted from the publications searched from the databases of EMBASE, Medline (Ovid SP), Web of Science, Cochrane library, PubMed Publisher, ASCO meeting abstract and Google Scholar before August 2016, or identified from the database of Shanghai Chest Hospital from July 2014 to August 2016...
February 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#12
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28426123/cabozantinib-in-hepatocellular-carcinoma-results-of-a-phase-2-placebo-controlled-randomized-discontinuation-study
#13
R K Kelley, C Verslype, A L Cohn, T-S Yang, W-C Su, H Burris, F Braiteh, N Vogelzang, A Spira, P Foster, Y Lee, E Van Cutsem
Background: Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts. Patients and methods: Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily...
March 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28426106/afatinib-versus-gefitinib-in-patients-with-egfr-mutation-positive-advanced-non-small-cell-lung-cancer-overall-survival-data-from-the-phase-iib-lux-lung-7-trial
#14
L Paz-Ares, E-H Tan, K O'Byrne, L Zhang, V Hirsh, M Boyer, J C-H Yang, T Mok, K H Lee, S Lu, Y Shi, D H Lee, J Laskin, D-W Kim, S A Laurie, K Kölbeck, J Fan, N Dodd, A Märten, K Park
Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R)...
February 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28425312/activation-of-spinal-alpha-7-nicotinic-acetylcholine-receptor-shortens-the-duration-of-remifentanil-induced-postoperative-hyperalgesia-by-upregulating-kcc2-in-the-spinal-dorsal-horn-in-rats
#15
Wei Gu, Wei Zhang, Yishan Lei, Yin Cui, Shuaishuai Chu, Xiaoping Gu, Zhengliang Ma
Background Accumulating evidence has shown that the signal from spinal brain-derived neurotrophic factor/tyrosine receptor kinase B-K(+)-Cl(-) cotransporter-2 plays a critical role in the process of pain hypersensitivity. The activation of alpha-7 nicotinic acetylcholine receptors could have an analgesic effect on remifentanil-induced postoperative hyperalgesia. Nevertheless, whether intrathecal administration of PNU-120596, an alpha-7 nicotinic acetylcholine receptors selective type II positive allosteric modulator, before surgery could affect the duration of remifentanil-induced postoperative hyperalgesia remains unknown, and the effects of alpha-7 nicotinic acetylcholine receptors activation on the brain-derived neurotrophic factor/tyrosine receptor kinase B-K(+)-Cl(-) cotransporter-2 signal in the spinal dorsal horn of rats with remifentanil-induced postoperative hyperalgesia is still enigmatic...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28424775/second-line-treatment-of-non-small-cell-lung-cancer-focus-on-the-clinical-development-of-dacomitinib
#16
REVIEW
Jon Zugazagoitia, Asunción Díaz, Elisabeth Jimenez, Juan Antonio Nuñez, Lara Iglesias, Santiago Ponce-Aix, Luis Paz-Ares
Dacomitinib is a second-generation, irreversible, covalent pan-HER tyrosine-kinase inhibitor (TKI). It showed potent EGFR signaling inhibition in experimental models, including first-generation TKI-resistant non-small cell lung cancer (NSCLC) cell lines. This preclinical efficacy did not translate into clinically meaningful treatment benefits for advanced, pretreated, molecularly unselected NSCLC patients enrolled in two parallel phase III trials. Dacomitinib and erlotinib showed overlapping efficacy data in chemotherapy-pretreated EGFR wild-type (WT) patients in the ARCHER 1009 trial...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28424757/the-emerging-role-of-targeted-therapy-and-immunotherapy-in-the-management-of-brain-metastases-in-non-small-cell-lung-cancer
#17
REVIEW
Annick Wong
Lung cancer is the worldwide leading cause of cancer-related mortality in men and second leading in women. Brain metastases (BM) account for 10% of non-small cell lung cancer (NSCLC) patients at initial presentation, with another 25-40% developing BM during the course of their disease. In the last decade, the field of precision oncology has led to the discovery of a multitude of heterogenous molecular abnormalities within NSCLC as well as the development of tyrosine kinase inhibitors that target them. In this review, the focus will be on targeted therapy and immunotherapy that show efficacy in BM rather than conventional treatment for multiple BM (such as surgical resection, WBRT, or stereotactic radiosurgery)...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28424749/development-of-asymmetric-facial-depigmentation-in-a-patient-treated-with-dasatinib-with-new-onset-hypovitaminosis-d-case-report-and-review-of-the-literature
#18
Kirsten C Webb, Magdalena Harasimowicz, Monica Janeczek, Jodi Speiser, James Swan, Rebecca Tung
Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) used to treat imatinib-resistant chronic myelogenous leukemia (CML), as well as other Philadelphia chromosome-positive lymphoproliferative disorders. While the most commonly reported cutaneous side effects with this therapy include a morbilliform eruption, skin exfoliation, and skin irritation, pigmentary abnormalities have also been observed, albeit much more rarely. We present the case of a 72-year-old South Asian male with CML who presented with new-onset hypopigmentation of his face and scalp three years after a dose increase of dasatinib therapy, in the setting of newly discovered borderline hypovitaminosis D...
2017: Case Reports in Dermatological Medicine
https://www.readbyqxmd.com/read/28424554/arterial-stiffness-in-hematologic-malignancies
#19
REVIEW
Ioana Mozos, Georgiana Borzak, Alexandru Caraba, Rodica Mihaescu
Malignant and cardiovascular disorders are the top causes of mortality worldwide. This article reviews the main literature data and mechanisms linking hematologic malignancies and arterial stiffness, focusing on recent experimental and clinical results. Several links were found in hematologic malignancies between complete blood count and arterial stiffness. Chemotherapy, especially anthracyclines, cyclophosphamide and tyrosine kinase inhibitors, as well as radiotherapy and hematopoietic stem cell transplantation are the main known causes of arterial stiffness increase in hematologic malignancies...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28424405/the-bruton-s-tyrosine-kinase-inhibitor-ibrutinib-exerts-immunomodulatory-effects-through-regulation-of-tumor-infiltrating-macrophages
#20
Lingyan Ping, Ning Ding, Yunfei Shi, Lixia Feng, Jiao Li, Yalu Liu, Yufu Lin, Cunzhen Shi, Xing Wang, Zhengying Pan, Yuqin Song, Jun Zhu
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has demonstrated promising efficacy in a variety of hematologic malignancies. However, the precise mechanism of action of the drug remains to be fully elucidated. Tumor-infiltrating macrophages presented in the tumor microenvironment have been shown to promote development and progression of B-cell lymphomas through crosstalk mediated by secreted cytokines and chemokines. Because Btk has been implicated in Toll-like receptor (TLR) signaling pathways that regulate macrophage activation and production of proinflammatory cytokines, we investigated the immunomodulatory effects of Btk inhibitor on macrophages...
April 5, 2017: Oncotarget
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