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https://www.readbyqxmd.com/read/28942039/comparative-effect-of-imatinib-and-ponatinib-on-autophagy-and-mirnome-in-chronic-myeloid-leukemia
#1
Cagla Kayabasi, Tugce Balci Okcanoglu, Besra Ozmen Yelken, Aycan Asik, Sunde Yilmaz Susluer, Cigir Biray Avci, Guray Saydam, Cumhur Gunduz
BCR-ABL tyrosine kinase inhibitors (TKIs) are selective therapies for the patients with Chronic Myeloid Leukemia (CML). Imatinib and ponatinib have remarkable long-term efficacy on a major molecular response. Although TKI related induction of cytotoxicity and apoptosis have been clearly investigated in molecular levels, their comparative effect on autophagy and miRNome are largely unknown. This study aimed to investigate the involvement of alterations of miRNA expressions in CML progression, and how imatinib and ponatinib affect this process, by comparing CML, imatinib-resistant CML and leukemia stem cells (LSC)...
September 20, 2017: Gene
https://www.readbyqxmd.com/read/28942004/leptomycin-b-reduces-primary-and-acquired-resistance-of-gefitinib-in-lung-cancer-cells
#2
Zhongwei Liu, Weimin Gao
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib has demonstrated dramatic clinical efficacy in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is ultimately limited by the development of acquired drug resistance. The aim of this study was to explore the potential utility of chromosome region maintenance 1 (CRM1) inhibitor leptomycin B (LMB) in combination with gefitinib to overcome primary and acquired gefitinib resistance in NSCLC cells. The combinative effects of gefitinib and LMB were evaluated by MTT and its underlining mechanism was assessed by flow cytometry and Western blot...
September 20, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28932544/the-detectability-of-the-pretreatment-egfr-t790m-mutations-in-lung-adenocarcinoma-using-cast-pcr-and-digital-pcr
#3
Tsutomu Tatematsu, Katsuhiro Okuda, Ayumi Suzuki, Risa Oda, Tadashi Sakane, Osamu Kawano, Hiroshi Haneda, Satoru Moriyama, Hidefumi Sasaki, Ryoichi Nakanishi
BACKGROUND: A gatekeeper T790M mutation is thought to cause resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. The detection of a 2nd mutation is important for planning the next therapy when patients acquire resistance to the first line EGFR-TKI. METHODS: We used a competitive allele-specific polymerase chain reaction (CAST-PCR) to analyze the incidence and clinical significance of T790M mutations in 153 lung adenocarcinomas with EGFR-activating mutations...
August 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28927112/non-small-cell-lung-cancer-pc-9-cells-exhibit-increased-sensitivity-to-gemcitabine-and-vinorelbine-upon-acquiring-resistance-to-egfr-tyrosine-kinase-inhibitors
#4
Junko Hamamoto, Hiroyuki Yasuda, Kaito Aizawa, Makoto Nishino, Shigenari Nukaga, Toshiyuki Hirano, Ichiro Kawada, Katsuhiko Naoki, Tomoko Betsuyaku, Kenzo Soejima
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) are widely used for the treatment of non-small cell lung cancers (NSCLCs) harboring EGFR-activating mutations. However, lung cancer cells inevitably acquire resistance to these EGFR-TKIs. The majority of patients whose lung cancer acquires resistance to EGFR-TKIs are subjected to treatment using cytotoxic agents. The present study aimed to determine if lung cancer cells acquiring resistance to EGFR-TKIs also develop altered sensitivity to cytotoxic agents...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28915640/marsdenia-tenacissima-extract-overcomes-axl-and-met-mediated-erlotinib-and-gefitinib-cross-resistance-in-non-small-cell-lung-cancer-cells
#5
Shu-Yan Han, Wei Zhao, Hai-Bo Han, Hong Sun, Dong Xue, Yan-Na Jiao, Xi-Ran He, Shan-Tong Jiang, Ping-Ping Li
Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non-small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915593/a-novel-egfr-tki-inhibitor-camp-h3bo3complex-combined-with-thermal-therapy-is-a-promising-strategy-to-improve-lung-cancer-treatment-outcomes
#6
Yongpeng Tong, Chunliu Huang, Junfang Zhang
PURPOSE: Although EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) induce favorable responses as first-line non-small cell lung cancer treatments, drug resistance remains a serious problem. Meanwhile, thermal therapy also shows promise as a cancer therapy strategy. Here we combine a novel EGFR-TKI treatment with thermal therapy to improve lung cancer treatment outcomes. RESULTS: The results suggest that the cAMP-H3BO3 complex effectively inhibits EGFR auto-phosphorylation, while inducing apoptosis and cell cycle arrest in vitro...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914261/rsk2-is-a-new-pim2-target-with-pro-survival-functions-in-flt3-itd-positive-acute-myeloid-leukemia
#7
M-A Hospital, A Jacquel, F Mazed, E Saland, C Larrue, J Mondesir, R Birsen, A S Green, M Lambert, P Sujobert, E-F Gautier, V Salnot, M Le Gall, J Decroocq, L Poulain, N Jacque, M Fontenay, O Kosmider, C Récher, P Auberger, P Mayeux, D Bouscary, J-E Sarry, J Tamburini
Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation...
September 15, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28911086/large-scale-prospective-screening-of-egfr-mutations-in-the-blood-of-advanced-nsclc-patients-to-guide-treatment-decisions
#8
C Mayo-de-Las-Casas, N Jordana-Ariza, M Garzón-Ibañez, A Balada-Bel, J Bertrán-Alamillo, S Viteri-Ramírez, N Reguart, M A Muñoz-Quintana, P Lianes-Barragan, C Camps, E Jantús, J Remon-Massip, S Calabuig, D Aguiar, M L Gil, N Viñolas, A K Santos-Rodríguez, M Majem, B García-Peláez, S Villatoro, A Pérez-Rosado, J C Monasterio, E Ovalle, M J Catalán, R Campos, D Morales-Espinosa, A Martínez-Bueno, M González-Cao, X González, I Moya-Horno, A E Sosa, N Karachaliou, R Rosell, M A Molina-Vila
Background: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Patients and methods: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue...
September 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28903416/overriding-tki-resistance-of-renal-cell-carcinoma-by-combination-therapy-with-il-6-receptor-blockade
#9
Kei Ishibashi, Tobias Haber, Ines Breuksch, Susanne Gebhard, Takashi Sugino, Hitoshi Kubo, Junya Hata, Tomoyuki Koguchi, Michihiro Yabe, Masao Kataoka, Soichiro Ogawa, Hiroyuki Hiraki, Tomohiko Yanagida, Nobuhiro Haga, Joachim W Thüroff, Dirk Prawitt, Walburgis Brenner, Yoshiyuki Kojima
Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28902850/copy-number-variation-analysis-in-cytochromes-and-glutathione-s-transferases-may-predict-efficacy-of-tyrosine-kinase-inhibitors-in-chronic-myeloid-leukemia
#10
Alexander V Lavrov, Oksana A Ustaeva, Elmira P Adilgereeva, Svetlana A Smirnikhina, Ekaterina Y Chelysheva, Oleg A Shukhov, Yuriy V Shatokhin, Sergey V Mordanov, Anna G Turkina, Sergey I Kutsev
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR/ABL fusion gene in leukemic cells, which promotes uncontrolled cell proliferation. Up to 20% of CML patients show primary resistance or non-optimal response to tyrosine kinase inhibitor (TKI) therapy. We investigated the association between copy number variation (CNV) in glutathione S-transferases (GST) and cytochromes (CYP) and the response rate to TKI. We enrolled 47 patients with CML: 31 with an optimal response and 16 with failure at 6 months in accordance with European LeukemiaNet 2013 recommendations...
2017: PloS One
https://www.readbyqxmd.com/read/28901317/k-ras-mutation-and-resistance-to-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor-treatment-in-patients-with-nonsmall-cell-lung-cancer
#11
Bin Zhou, Congrong Tang, Jie Li
OBJECTIVE: The aim of this study was to evaluate the relationship between k-RAS gene mutation and the resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with nonsmall-cell lung cancer (NSCLC). METHODS: Forty-five pathologies confirmed NSCLC patients who received EGFR-TKI (Gefitinib) treatment were retrospectively included in this study. The mutation of codon 12 and 13, located in exon1 and exon 2 of k-RAS gene were examined by polymerase chain reaction (PCR) and DAN sequencing in tumor samples of the included 45 NSCLC patients...
2017: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/28900984/-targeted-therapy-combined-with-immunotherapy-in-gastrointestinal-stromal-tumor-a-new-era-of-hope-and-challenges
#12
Wenyi Zhao, Hui Cao
New immunotherapy represented by immune checkpoint inhibitor therapy and chimeric antigen receptor T-Cell immunotherapy (CAR-T) has already become hot trend in the treatment of malignant tumors. In gastrointestinal stromal tumor (GIST), with notable tumor-infiltrating immune cells existing in GIST tissues and immunological effects reported in imatinib mesylate (IM) treatment, the clinicians and researchers started to realize the possibilities of immunotherapy in GIST. Recent studies reported that PD-1/PD-L1 or CTLA-4 blockade may enhance the T-cell activity and anti-tumor effect of targeted therapy, which can be applied in advanced GIST, and anti-KIT CAR T-cells indicated a new immunotherapeutic targeted strategy for GIST patients with TKI resistance...
September 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/28892778/an-increase-in-bag-1-by-pd-l1-confers-resistance-to-tyrosine-kinase-inhibitor-in-non-small-cell-lung-cancer-via-persistent-activation-of-erk-signalling
#13
Po-Lin Lin, Tzu-Chin Wu, De-Wei Wu, Lee Wang, Chi-Yi Chen, Huei Lee
High programmed cell death 1 ligand 1 (PD-L1) expression in tumour tissues was associated with poor outcomes in non-small cell lung cancer (NSCLC) due to evasion of tumour immune surveillance. However, the role of PD-L1 in tumour invasion and resistance to tyrosine kinase inhibitor (TKI) treatments is not fully understood. Here, we provide evidence to support the involvement of PD-L1 expression in the invasiveness and TKI resistance in NSCLC cells by increased Bcl-2-associated athanogene-1 (BAG-1) expression...
September 8, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28888102/a-new-mechanism-of-resistance-to-abl1-tyrosine-kinase-inhibitors-in-a-bcr-abl1-positive-cell-line
#14
Kelly Airiau, Béatrice Turcq, François-Xavier Mahon, Francis Belloc
Tyrosine kinase inhibitors (TKI) constitute the frontline treatment for chronic myeloid leukemia patients. Dasatinib, a second-generation TKI, was developed to overcome TKI resistances. However, dasatinib resistances are also described but remain less characterized. To mimic in vivo acquired dasatinib resistance, the BCR-ABL1-positive cell line K562 was transiently treated with a pharmacological concentration of dasatinib, for a short time in the presence of stem cell factor. A dasatinib resistant counterpart (K562 RES) was developed...
August 31, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28881711/characterization-of-midostaurin-as-a-dual-inhibitor-of-flt3-and-syk-and-potentiation-of-flt3-inhibition-against-flt3-itd-driven-leukemia-harboring-activated-syk-kinase
#15
Ellen L Weisberg, Alexandre Puissant, Richard Stone, Martin Sattler, Sara J Buhrlage, Jing Yang, Paul W Manley, Chengcheng Meng, Michael Buonopane, John F Daley, Suzan Lazo, Renee Wright, David M Weinstock, Amanda L Christie, Kimberly Stegmaier, James D Griffin
Oncogenic FLT3 kinase is a clinically validated target in acute myeloid leukemia (AML), and both multi-targeted and selective FLT3 inhibitors have been developed. Spleen tyrosine kinase (SYK) has been shown to be activated and increased in FLT3-ITD-positive AML patients, and has further been shown to be critical for transformation and maintenance of the leukemic clone in these patients. Further, over-expression of constitutively activated SYK causes resistance to highly selective FLT3 tyrosine kinase inhibitors (TKI)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881589/decreased-calpain-activity-in-chronic-myeloid-leukemia-impairs-apoptosis-by-increasing-survivin-in-myeloid-progenitors-and-xiap1-in-differentiating-granulocytes
#16
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...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28879074/a-case-report-of-egfr-mutant-lung-adenocarcinoma-that-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-with-t790m-mutation-and-epithelial-to-mesenchymal-transition
#17
Nana Zhang, Depu Wang, Xiaofeng Li, Zhe Yang, Guanjun Zhang, Yili Wang, Chunbao Wang
Although a secondary mutation and the epithelial-to-mesenchymal transition (EMT) are encountered very often in patients received the EGFR-TKI targeted treatment. The entire detrimental morphological change of the cancer entity was rare reported. Herein we report a case that acquired resistance to EGFR-TKI with T790M mutation and complete EMT morphological change of the tumor tissue. The primary lung tumor from a 52-year-old woman was diagnosed with moderate differentiated adenocarcinoma, with intensively positiveTTF-1 and E-cadherin in differentiated glandular structure but not the budding cancer cell cluster which with an intensive Vimentin staining...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28874695/deep-phospho-and-phosphotyrosine-proteomics-identified-active-kinases-and-phosphorylation-networks-in-colorectal-cancer-cell-lines-resistant-to-cetuximab
#18
Yuichi Abe, Maiko Nagano, Takahisa Kuga, Asa Tada, Junko Isoyama, Jun Adachi, Takeshi Tomonaga
Abnormality in cellular phosphorylation is closely related to oncogenesis. Thus, kinase inhibitors, especially tyrosine kinase inhibitors (TKIs), have been developed as anti-cancer drugs. Genomic analyses have been used in research on TKI sensitivity, but some types of TKI resistance have been unclassifiable by genomic data. Therefore, global proteomic analysis, especially phosphotyrosine (pY) proteomic analysis, could contribute to predict TKI sensitivity and overcome TKI-resistant cancer. In this study, we conducted deep phosphoproteomic analysis to select active kinase candidates in colorectal cancer intrinsically resistant to Cetuximab...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28870456/pharmacological-synergism-of-2-2-dichloroacetophenone-and-egfr-tki-to-overcome-tki-induced-resistance-in-nsclc-cells
#19
Zheng Yang, Xiaohui Hu, Shaolin Zhang, Wen Zhang, Kin Yip Tam
Combination treatment has been used as one of the therapeutic approaches for patients suffering from lung cancer, either to cope with the issue of acquired drug resistance due to prolong the use of a particular EGFR-TKi treatment, or to decrease the doses of each compound in order to reduce potential toxicity. 2,2-dichloroacetophenone (DAP) was reported as a PDK inhibitor recently, which is much more potent than dichloroacetate (DCA) in anti-cancer therapy. In this study, we applied DAP in combined with EGFR-TKis, erlotinib or gefitinib in NSCLC cell lines and NSCLC xenograft model...
September 11, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28868565/comparison-of-the-amplification-refractory-mutation-system-super-amplification-refractory-mutation-system-and-droplet-digital-pcr-for-t790%C3%A2-m-mutation-detection-in-non-small-cell-lung-cancer-after-failure-of-tyrosine-kinase-inhibitor-treatment
#20
Lucheng Zhu, Shirong Zhang, Yanping Xun, Yanping Jiang, Bing Xia, Xueqin Chen, Limin Wang, Hong Jiang, Shenglin Ma
Plasma mutation detection has the advantages of non-invasiveness and accessibility. Here, we evaluated three methods, the amplification refractory mutation system (ARMS), second-generation ARMS (SuperARMS), and droplet digital PCR (ddPCR), to assess their concordance and feasibility for the detection of mutations in plasma samples. Non-small lung cancer patients with stage IIIB/IV that were resistant to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment were enrolled. Blood samples were collected within 14 days after TKI resistance...
September 3, 2017: Pathology Oncology Research: POR
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