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https://www.readbyqxmd.com/read/29149649/chk1-inhibitors-overcome-imatinib-resistance-in-chronic-myeloid-leukemia-cells
#1
Hu Lei, Jin Jin, Meng Liu, Xiangyun Li, Hao Luo, Li Yang, Hanzhang Xu, Yingli Wu
Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem of chronic myelogenous leukemia (CML). Bcr-Abl protein depletion is considered as a way to overcome drug resistance to TKIs. In our study, Chk1 inhibitors, AZD7762 and MK-8776, had strong antitumor effects on CML cell line KBM5 and imatinib-resistant form KBM5(T315I). Moreover, Chk1 inhibitors showed a strong cytotoxic effect on leukemia cells from primary CML and imatinib-resistance CML patients, but low cytotoxic effect on normal human mononuclear cells...
November 11, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29145240/gastrointestinal-stromal-tumor-gist-with-liver-metastases-an-18-year-experience-from-the-gist-cooperation-group-in-north-china
#2
Yi-Nan Shi, Yong Li, Li-Ping Wang, Zhen-Hua Wang, Xiao-Bo Liang, Han Liang, Li Zhang, Bin Li, Li-Qiao Fan, Qun Zhao, Zhi-Xue Ma, Xue-Feng Zhao, Zhi-Dong Zhang, Yu Liu, Bi-Bo Tan, Dong Wang, Li-Li Wang, Ying-Jie Hao, Nan Jia
Approximately 40% to 50% of gastrointestinal stromal tumor (GIST) patients will have recurrence or metastases after resection of the primary lesion, and the most common affected sites will be liver and peritoneum. Imatinib has been considered as the first-line therapy of metastatic GIST. Surgery for metastases is proposed when possible. Furthermore, there are controversies concerning hepatic resection and systemic tyrosin kinase inhibitors (TKIs). The therapeutic conditions and long-term outcome of GIST patients with liver metastases in northern China remain unknown...
November 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29143897/anaplastic-lymphoma-kinase-testing-ihc-vs-fish-vs-ngs
#3
REVIEW
Xiaomin Niu, Jody C Chuang, Gerald J Berry, Heather A Wakelee
Personalized targeted therapy has emerged as a promising strategy in lung cancer treatment, with current attention focused on elucidation and detection of oncogenic drivers responsible for tumor initiation and maintenance and development of drug resistance. In lung cancer, several oncogenic drivers have been reported, triggering the application of tyrosine kinase inhibitors (TKIs) to target these dysfunctional genes. The anaplastic lymphoma kinase (ALK) rearrangement is responsible for about 4-7% of all non-small cell lung cancers (NSCLCs) and perhaps as high as a third in specific patient populations such as younger, male, non-smokers with advanced stage, epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) wild type, and signet ring cell adenocarcinoma with abundant intracytoplasmic mucin...
November 16, 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/29143497/detection-and-monitoring-of-driver-mutations-by-next-generation-sequencing-in-squamous-cell-lung-cancer-patient-and-possible-predictive-biomarker-of-third-generation-egfr-tyrosine-kinase-inhibitors
#4
Xiaoyan Shen, Jie Shen, Hang Zhang, Yuxin Cheng, Yang Yang, Jiahui Gao, Yu Zhang, Rutian Li, Baorui Liu, Lifeng Wang
Driver mutation detection and the development of targeted drugs have significantly improved survival of advanced lung adenocarcinoma patients with driver mutations. However, we still lack understanding of druggable mutations in patients with advanced squamous cell lung cancer (SQCLC). Less than 10% of SQCLC patients have EGFR gene mutations, thus we have limited knowledge of biological molecular changes with first generation EGFR-tyrosine kinase inhibitor (TKI) resistance. We report a case of an SQCLC patient treated with first-line platinum-doublet chemotherapy...
November 16, 2017: Thoracic Cancer
https://www.readbyqxmd.com/read/29141884/a-method-of-high-throughput-functional-evaluation-of-egfr-gene-variants-of-unknown-significance-in-cancer
#5
Shinji Kohsaka, Masaaki Nagano, Toshihide Ueno, Yoshiyuki Suehara, Takuo Hayashi, Naoko Shimada, Kazuhisa Takahashi, Kenji Suzuki, Kazuya Takamochi, Fumiyuki Takahashi, Hiroyuki Mano
Numerous variants of unknown significance (VUS) have been identified through large-scale cancer genome projects, although their functional relevance remains uninvestigated. We developed a mixed-all-nominated-mutants-in-one (MANO) method to evaluate the transforming potential and drug sensitivity of oncogene VUS in a high-throughput manner and applied this method to 101 nonsynonymous epidermal growth factor receptor (EGFR) mutants. We discovered a number of mutations conferring resistance to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib- and erlotinib-insensitive missense mutations within exon 19 and other gefitinib-resistant mutations, such as L833V, A839T, V851I, A871T, and G873E...
November 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29137977/downregulation-of-caveolin-1-increased-egfr-tkis-sensitivity-in-lung-adenocarcinoma-cell-line-with-egfr-mutation
#6
Yujie Cui, Tienian Zhu, Xuejing Song, Jiankun Liu, Shuang Liu, Ruijing Zhao
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have shown notable effects in lung adenocarcinoma patients harboring EGFR mutations, there are significant differences between individual patients in the degree of benefits provided by EGFR-TKIs. Some evidence supports a role for caveolin-1 (Cav-1) in modulating drug sensitivity. This study aimed to investigate whether Cav-1 plays an important role in sensitivity to EGFR-TKIs in lung adenocarcinoma cells...
November 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29137227/re-balance-of-memory-t-cell-subsets-in-peripheral-blood-from-patients-with-cml-after-tki-treatment
#7
Danlin Yao, Ling Xu, Jiaxiong Tan, Yikai Zhang, Shuai Lu, Mingde Li, Sichun Lu, Lijian Yang, Shaohua Chen, Jie Chen, Jing Lai, Yuhong Lu, Xiuli Wu, Xianfeng Zha, Yangqiu Li
T cell immune surveillance is considered an important host protection process for inhibiting carcinogenesis. The full capacity of T cell immune surveillance is dependent on T cell homeostasis, particularly for central memory T (TCM) cells and stem cell memory T (TSCM) cells. In this study, distribution of T cell subsets in peripheral blood from 12 patients with chronic myeloid leukemia (CML) and 12 cases with CML in complete remission (CR) was analyzed using a multicolor flow cytometer, and 16 samples from healthy individuals (HIs) served as control...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136529/yap-dependent-axl-overexpression-mediates-resistance-to-egfr-inhibitors-in-nsclc
#8
Elena Ghiso, Cristina Migliore, Vito Ciciriello, Elena Morando, Annalisa Petrelli, Simona Corso, Emmanuele De Luca, Gaia Gatti, Marco Volante, Silvia Giordano
The Yes-associated protein (YAP) is a transcriptional co-activator upregulating genes that promote cell growth and inhibit apoptosis. The main dysregulation of the Hippo pathway in tumors is due to YAP overexpression, promoting epithelial to mesenchymal transition, cell transformation, and increased metastatic ability. Moreover, it has recently been shown that YAP plays a role in sustaining resistance to targeted therapies as well. In our work, we evaluated the role of YAP in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in lung cancer...
November 11, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29136465/recent-progress-of-small-molecule-epidermal-growth-factor-receptor-egfr-inhibitors-against-c797s-resistance-in-non-small-cell-lung-cancer
#9
Lingfeng Chen, Weitao Fu, Lulu Zheng, Zhiguo Liu, Guang Liang
The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein797 to serine790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs...
November 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29128554/immunomodulatory-effects-of-tyrosine-kinase-inhibitors-tkis-in-vitro-and-in-vivo-study
#10
Elena Marinelli Busilacchi, Andrea Costantini, Nadia Viola, Benedetta Costantini, Jacopo Olivieri, Luca Butini, Giorgia Mancini, Ilaria Scortechini, Martina Chiarucci, Monica Poiani, Antonella Poloni, Pietro Leoni, Attilio Olivieri
Pathogenesis of chronic Graft Versus Host Disease (cGVHD) is incompletely defined, involving donor-derived CD4 and CD8-positive T lymphocytes, as well as B cells. Standard treatment is lacking for steroid dependent/refractory cases; potential usefulness of tyrosine kinase inhibitors (TKIs) has been suggested, based on their potent anti-fibrotic effect. However, TKI seems to have pleiotropic activity. We sought to evaluate the in vitro and in vivo impact of different TKIs on lymphocyte phenotype and function...
November 8, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29123416/frequency-and-clinical-relevance-of-egfr-mutations-and-eml4-alk-translocations-in-octogenarians-with-non-small-cell-lung-cancer
#11
Amanda Tufman, Kathrin Kahnert, Thomas Duell, Diego Kauffmann-Guerrero, Katrin Milger, Christian Schneider, Julia Stump, Zulfiya Syunyaeva, Rudolf Maria Huber, Simone Reu
Background: Tyrosine kinase inhibitors (TKIs) have improved response rates in some patients with non-small cell lung cancer (NSCLC), and testing for EGFR mutation and ALK translocation is recommended for all patients with advanced lung adenocarcinoma. The frequency of driver mutations in elderly and very elderly patients has not been described. Patients and methods: We reviewed EGFR and ALK in patients over the age of 70 years diagnosed and treated at our center in 2015 (subgroups: 70-74, 75-79 and >80 years)...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29121501/does-c-met-remain-a-rational-target-for-therapy-in-patients-with-egfr-tki-resistant-non-small-cell-lung-cancer
#12
REVIEW
Yi-Long Wu, Ross Andrew Soo, Giuseppe Locatelli, Uz Stammberger, Giorgio Scagliotti, Keunchil Park
Non-small cell lung cancer (NSCLC) inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. In 5-20% of cases, this can be attributed to aberrant c-Met activity, providing a clear rationale for the use of c-Met inhibitors in these patients. EGFR TKI-resistant tumors often remain sensitive to EGFR signaling, such that c-Met inhibitors are likely to be most effective when combined with continued EGFR TKI therapy. The phase III trials of the c-Met inhibitors onartuzumab and tivantinib, which failed to demonstrate significant benefit in patients with NSCLC but excluded patients with EGFR TKI-resistant disease, do not allow c-Met to be dismissed as a rational target in EGFR TKI-resistant NSCLC...
October 25, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29121435/altered-intracellular-signaling-by-imatinib-increases-the-anti-cancer-effects-of-tyrosine-kinase-inhibitors-in-cml-cells
#13
Takuya Hirao, Masashi Yamaguchi, Megumi Kikuya, Hiroji Chibana, Kousei Ito, Shigeki Aoki
Tyrosine kinase inhibitors (TKIs), including imatinib (IM), improve the outcome of chronic myelogenous leukemia (CML) therapy. However, TKI treatment is long-term and can induce resistance to TKIs, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome-positive CML cell line, and its subsequent sensitivity to anti-cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKIs...
November 9, 2017: Cancer Science
https://www.readbyqxmd.com/read/29120911/immunotherapy-for-kidney-cancer-status-quo-and-the-future
#14
Jens Bedke, Viktoria Stühler, Arnulf Stenzl, Bernhard Brehmer
PURPOSE OF REVIEW: The treatment landscape in advanced and metastatic renal cell carcinoma (RCC) is moving from the inhibition of tyrosine kinases (TKI) and the mammalian target of rapamycin (mTOR) inhibitors to specific immunooncology agents like immune checkpoint inhibitors (ICI). The review focus on the recent immunooncology developments and available trial results within the last 12 months. RECENT FINDINGS: ICI as monotherapy (nivolumab) or immunooncology and immunooncology combinations (nivolumab and ipilimumab) demonstrated positive results on prolonged overall survival in phase III trials...
November 7, 2017: Current Opinion in Urology
https://www.readbyqxmd.com/read/29120087/histological-evolution-from-primary-lung-adenocarcinoma-harboring-egfr-mutation-to-high-grade-neuroendocrine-carcinoma
#15
Jikai Zhao, Jinchen Shao, Ruiying Zhao, Rong Li, Keke Yu, Lei Zhu, Jie Zhang
BACKGROUND: Although patients with EGFR mutated lung adenocarcinoma benefit greatly from tyrosine kinase inhibitors (TKIs), they inevitably develop acquired resistance after an average of 10-14 months of continuous treatment. METHODS: We retrospectively analyzed the clinical and histopathological data of eight patients with primary lung adenocarcinoma harboring EGFR mutations that transformed into high-grade neuroendocrine carcinoma after TKI therapy. Morphology scanning for neuroendocrine differentiation and immunohistochemistry for neuroendocrine markers CD56, chromogranin, and synaptophysin were performed on primary adenocarcinoma tissues and repeated biopsies...
November 9, 2017: Thoracic Cancer
https://www.readbyqxmd.com/read/29119113/increased-egfr-phosphorylation-correlates-with-higher-programmed-death-ligand-1-expression-analysis-of-tki-resistant-lung-cancer-cell-lines
#16
Kenichi Suda, Leslie Rozeboom, Koh Furugaki, Hui Yu, Mary Ann C Melnick, Kim Ellison, Christopher J Rivard, Katerina Politi, Tetsuya Mitsudomi, Fred R Hirsch
Despite the recent development of immunotherapies that target programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) treatment, these therapies are less effective in NSCLC patients with epidermal growth factor receptor (EGFR) mutations. However, the molecular mechanisms underlying this lower efficacy of immunotherapies in EGFR mutant lung cancers are still unclear. In this study, we analyzed PD-L1 protein expression in lung cancer cell lines with EGFR mutations prior to and after acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs)...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29118262/stress-hormones-promote-egfr-inhibitor-resistance-in-nsclc-implications-for-combinations-with-%C3%AE-blockers
#17
Monique B Nilsson, Huiying Sun, Lixia Diao, Pan Tong, Diane Liu, Lerong Li, Youhong Fan, Alissa Poteete, Seung-Oe Lim, Kathryn Howells, Vincent Haddad, Daniel Gomez, Hai Tran, Guillermo Armaiz Pena, Lecia V Sequist, James C Yang, Jing Wang, Edward S Kim, Roy Herbst, J Jack Lee, Waun Ki Hong, Ignacio Wistuba, Mien-Chie Hung, Anil K Sood, John V Heymach
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance mediated by T790M-independent mechanisms remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). We identified a targetable mechanism of EGFR inhibitor resistance whereby stress hormones activate β2-adrenergic receptors (β2-ARs) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce interleukin-6 (IL-6) expression...
November 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29115640/off%C3%A2-target-effect-of-imatinib-and-nilotinib-on-human-vitamin-d3-metabolism
#18
Lysann Kroschwald, Meinolf Suttorp, Josephine Tabea Tauer, Nick Zimmermann, Claudia Günther, Andrea Bauer
Prolonged treatment with tyrosine kinase inhibitors (TKI) including imatinib (IMA) or nilotinib (NIL), induces severe disturbances of bone metabolism in patients with chronic myeloid leukaemia. As vitamin D3 (VD3) is involved in the complex cycle of bone remodelling, the present study investigated in vitro, the influence of IMA and NIL on VD3 metabolism i) in HaCaT cells and ii) in cultured outer root sheath keratinocytes (ORS‑KC) from hair follicles of IMA treated children. Cells were incubated in the presence of IMA or NIL...
November 3, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29113396/epidermal-growth-factor-receptor-is-associated-with-the-onset-of-skeletal-related-events-in-non-small-cell-lung-cancer
#19
Shu-Mei Huang, Jin-Ji Yang, Hua-Jun Chen, Si-Pei Wu, Xiao-Yan Bai, Qing Zhou, Hai-Yan Tu, Yi-Long Wu
Background: Bone metastasis and skeletal related events (SREs) are common in non-small cell lung cancer (NSCLC). Patients with mutant epidermal growth factor receptor (EGFR) could benefit from tyrosine kinase inhibitors (TKIs). However, it is unclear whether SRE is influenced by EGFR status. We aimed to evaluate the correlation of EGFR status and TKIs with the incidence of SREs. Methods: We conducted a retrospective study of stage IV NSCLC patients with bone metastasis...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29110841/heterogeneous-resistance-mechanisms-in-an-egfr-exon-19-mutated-non-small-cell-lung-cancer-patient-treated-with-erlotinib-persistent-fgfr3-mutation-localized-transformation-to-egfr-mutated-sclc-and-acquired-t790m-egfr-mutation
#20
Eric Santoni-Rugiu, Morten Grauslund, Linea C Melchior, Junia C Costa, Jens B Sørensen, Edyta M Urbanska
Patients with epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer (NSCLC) obtain substantial clinical benefit from EGFR tyrosine-kinase inhibitors (TKIs), but will ultimately develop TKI-resistance resulting in median progression-free survival of 9-15 months during first-line TKI-therapy. However, type and timing of TKI-resistance cannot be predicted and several mechanisms may simultaneously/subsequently occur during TKI-treatment. In this respect, we present a 49 year-old Caucasian male ex-smoker with metastatic pulmonary adenocarcinoma (ADC) that concomitantly harbored an EGFR exon 19-mutation (p...
November 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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