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TKI resistance

Bo Zhang, Shuyuan Wang, Jie Qian, Wenjia Yang, Fangfei Qian, Jun Lu, Yanwei Zhang, Rong Qiao, Baohui Han
BACKGROUND: Two or more different epidermal growth factor receptor (EGFR) mutations can be detected within a single tumor sample, which represents complex mutations. However, the frequency and efficacy of tyrosine kinase inhibitor (TKI) treatments for patients harboring these mutations are unknown. METHODS: From January 2011 to January 2017, patients diagnosed with EGFR mutations were screened. The effectiveness of TKIs in patients with complex mutations was retrospectively analyzed...
March 15, 2018: Cancer
Ching-Yuan Kuo, Po-Nan Wang, Wen-Li Hwang, Cheng-Hwai Tzeng, Li-Yaun Bai, Jih-Luh Tang, Ming-Chih Chang, Sheng-Fung Lin, Tsai-Yun Chen, Yeu-Chin Chen, Tran-Der Tan, Chih-Yi Hsieh, Chinjune Lin, Clinton Lai, Darko Miljkovic, Cheng-Shyong Chang
Background: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is approved for the treatment of patients with chronic myeloid leukemia (CML) in many countries, including Taiwan. Though a number of controlled clinical trials have demonstrated the safety and efficacy of nilotinib, studies assessing the safety and efficacy of nilotinib in routine clinical practice are limited. Methods: The current study was an open-label, single-arm study conducted across 12 centers in Taiwan in adult patients with CML in chronic or accelerated phase with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to one or more previous TKIs...
March 2018: Therapeutic Advances in Hematology
Helena Yu, Ken Suzawa, Emmet J Jordan, Ahmet Zehir, Andy Ni, Hyunjae Ryan Kim, Mark G Kris, Matthew D Hellmann, Bob T Li, Romel Somwar, David B Solit, Michael F Berger, Maria E Arcila, Gregory J Riely, Marc Ladanyi
PURPOSE: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data...
March 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yongchang Lai, Zhijian Zhao, Tao Zeng, Xiongfa Liang, Dong Chen, Xiaolu Duan, Guohua Zeng, Wenqi Wu
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel-Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy...
2018: Cancer Cell International
Xiang Cao, Yi Zhou, Hongfang Sun, Miao Xu, Xiaowen Bi, Zhihui Zhao, Binghui Shen, Fengyi Wan, Zhuan Hong, Lei Lan, Lan Luo, Zhigang Guo, Zhimin Yin
Non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations initially respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and have shown favorable outcomes. However, acquired drug resistance to EGFR-TKIs develops in almost all patients mainly due to the EGFR T790 M mutation. Here, we show that treatment with low-dose EGFR-TKI results in the emergence of the EGFR T790 M mutation and in the reduction of HSP70 protein levels in HCC827 cells. Erlotinib treatment inhibits HSP70 phosphorylation at tyrosine 41 and increases HSP70 ubiquitination, resulting in HSP70 degradation...
March 7, 2018: Cancer Letters
Fulvio Massaro, Gioia Colafigli, Matteo Molica, Massimo Breccia
Chronic myeloid leukemia (CML) is characterized by a pathognomonic chromosomal translocation, which leads to the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus 1 (ABL1) genes, generating an oncoprotein with deregulated tyrosine kinase activity. Areas covered: In the last two decades, BCR/ABL1 kinase has become the molecular target for tyrosine kinase inhibitors (TKIs), a class of drugs that impressively improved overall survival. Despite these results, a proportion of patients experiences resistance to TKIs and need to change treatment...
March 9, 2018: Expert Review of Hematology
Pierre Laneuville
Strict criteria for when to stop tyrosine kinase inhibitor (TKI) therapy in clinical practice are not easily defined without an agreement on what probability of achieving a treatment-free remission (TFR) constitutes a medically acceptable standard and consideration of the potential medical risks of continued TKI therapy and/or patient preferences. Patients in sustained deep molecular response (DMR) have no significant chronic myelogenous leukemia-related risk of progression and death, and thus, safety is of paramount importance...
March 8, 2018: Current Treatment Options in Oncology
Bin Zou, Victor H F Lee, Hong Yan
BACKGROUND: Non-small cell lung cancer (NSCLC) with activating EGFR mutations, especially exon 19 deletions and the L858R point mutation, is particularly responsive to gefitinib and erlotinib. However, the sensitivity varies for less common and rare EGFR mutations. There are various explanations for the low sensitivity of EGFR exon 20 insertions and the exon 20 T790 M point mutation to gefitinib/erlotinib. However, few studies discuss, from a structural perspective, why less common mutations, like G719X and L861Q, have moderate sensitivity to gefitinib/erlotinib...
March 7, 2018: BMC Bioinformatics
Yu Zhu, Luo Lu, Chun Qiao, Yi Shan, Huapeng Li, Sixuan Qian, Ming Hong, Huihui Zhao, Jianyong Li, Zhongfa Yang, Yaoyu Chen
Resistance to the BCR-ABL tyrosine kinase inhibitor (TKI) remains a challenge for curing the disease in chronic myeloid leukemia (CML) patients as leukemia cells may survive through BCR-ABL kinase activity-independent signal pathways. To gain insight into BCR-ABL kinase activity-independent mechanisms, we performed an initial bioinformatics screen and followed by a quantitative PCR screen of genes that were elevated in CML samples. A total of 33 candidate genes were identified to be highly expressed in TKIs resistant patients...
March 7, 2018: Oncogene
Sébastien Rinaldetti, Markus Pfirrmann, Kirsi Manz, Joelle Guilhot, Christian Dietz, Panayiotidis Panagiotidis, Birgit Spiess, Wolfgang Seifarth, Alice Fabarius, Martin Müller, Maria Pagoni, Maria Dimou, Jolanta Dengler, Cornelius F Waller, Tim H Brümmendorf, Regina Herbst, Andreas Burchert, Carsten Janβen, Maria Elisabeth Goebeler, Philipp J Jost, Stefan Hanzel, Philippe Schafhausen, Gabriele Prange-Krex, Thomas Illmer, Viktor Janzen, Martine Klausmann, Robert Eckert, Gerd Büschel, Alexander Kiani, Wolf-Karsten Hofmann, François-Xavier Mahon, Susanne Saussele
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial...
February 8, 2018: Clinical Lymphoma, Myeloma & Leukemia
De-Wei Wu, Yao-Chen Wang, Lee Wang, Chih Yi Chen, Huei Lee
Purpose: MicroRNA-630 plays dual roles in apoptosis and drug resistance in human cancers. However, the role of miR-630 in resistance to tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma remains to be elucidated. Methods: Manipulation of miR-630 and its targeted gene YAP1 and/or combination of inhibitor treatments was performed to explore whether low miR-630 could confer TKI resistance due to de-targeting YAP1, and this could decrease proapoptotic protein Bad expression through the miR-630/YAP1/ERK feedback loop...
2018: Theranostics
Eric K Singhi, Leora Horn
Despite significant advancements in the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) since the advent of crizotinib, the development of acquired resistance and poor CNS efficacy have necessitated the search for novel and more robust therapies. Ensartinib (X-396) is a novel second-generation ALK-tyrosine kinase inhibitor (TKI) that holds much clinical promise. Preclinical data have demonstrated increased potency of the drug as compared with crizotinib and other second-generation ALK-TKI therapies such as alectinib and ceritinib...
March 6, 2018: Future Oncology
Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Katherine X Shaw, Satoshi Yoda, Grainne Kerr, Kristine Yu, Jinsheng Liang, Yichen Cao, Yan Chen, Michael S Lawrence, Adam Langenbucher, Justin F Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice T Shaw, Aaron N Hata, Cyril H Benes, Fang Li, Jeffrey A Engelman
Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited...
March 5, 2018: Nature Medicine
Bo Zhang, Jianlin Xu, Xueyan Zhang, Ping Gu, Huimin Wang, Shuyuan Wang, Jie Qian, Rong Qiao, Yanwei Zhang, Wenjia Yang, Fangfei Qian, Yan Zhou, Jun Lu, Lele Zhang, Baohui Han
OBJECTIVES: Occasionally, primary 20 T790M/insertion plus sensitive mutations can be detected within a single tumor sample by routine molecular testing, but the optimal clinical management for these patients is unclear. Herein, we determined the optimal treatment strategy for these patients. MATERIALS AND METHODS: From January 2011 to January 2017, patients diagnosed with epidermal growth factor receptor (EGFR) mutation were screened. For these harboring primary 20 T790M/insertion plus sensitive mutations, the effectiveness of the first or third generation tyrosine kinase inhibitors (TKIs) were retrospectively analyzed...
March 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Geeta Geeta Sharma, Ines Mota, Luca Mologni, Enrico Patrucco, Carlo Gambacorti-Passerini, Roberto Chiarle
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy...
February 28, 2018: Cancers
Juan Chen, Jie-da Cui, Xiao-Tong Guo, Xia Cao, Qing Li
Epidermal growth receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for advanced non-small-cell lung cancer (NSCLC) patients with EFGR mutations. However, most patients with NSCLC show acquired resistance to EGFR-TKIs, and low expression of NF1 is a mechanism of EGFR-TKI resistance in lung cancer. However, the mechanism by which NF1 is downregulated in EGFR-TKI-resistant NSCLC is unclear. Here, we found the increased expression of miR-641 in NSCLC cells and human NSCLC samples with resistance to TKI compared to those with sensitive to TKI...
March 1, 2018: Cancer Medicine
Anna Chorzalska, Nagib Ahsan, R Shyama Prasad Rao, Karim Roder, Xiaoqing Yu, John Morgan, Alexander Tepper, Steven Hines, Peng Zhang, Diana O Treaba, Ting C Zhao, Adam J Olszewski, John Reagan, Olin Liang, Philip A Gruppuso, Patrycja M Dubielecka
The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long-term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr-Abl1 protein and activity levels while maintaining proliferative potential...
February 27, 2018: Molecular Oncology
Po-Hao Feng, Chih-Teng Yu, Kuan-Yuan Chen, Ching-Shan Luo, Shen Ming Wu, Chien-Ying Liu, Lu Wei Kuo, Yao-Fei Chan, Tzu-Tao Chen, Chih-Cheng Chang, Chun-Nin Lee, Hsiao-Chi Chuang, Chiou-Feng Lin, Chia-Li Han, Wei-Hwa Lee, Kang-Yun Lee
Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS)...
January 26, 2018: Oncotarget
Doralina do Amaral Rabello, Vivian D'Afonseca da Silva Ferreira, Maria Gabriela Berzoti-Coelho, Sandra Mara Burin, Cíntia Leticia Magro, Maira da Costa Cacemiro, Belinda Pinto Simões, Felipe Saldanha-Araujo, Fabíola Attié de Castro, Fabio Pittella-Silva
Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm whose pathogenesis is linked to the Philadelphia chromosome presence that generates the BCR - ABL 1 fusion oncogene. Tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) dramatically improved the treatment efficiency and survival of CML patients by targeting BCR-ABL tyrosine kinase. The disease shows three distinct clinical-laboratory stages: chronic phase, accelerated phase and blast crisis...
2018: Cancer Cell International
Zheng Yang, Kin Yip Tam
Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired resistance inevitably occurs after long-term exposure. More recently, combination therapy has emerged as a promising strategy to overcome this issue. Several experiments have been carried out to evaluate the synergism of combination therapy both in vitro and in vivo . Additionally, many clinical studies have been carried out to investigate the feasibility of treatment with EGFR-tyrosine kinase inhibitors (TKi) combined with other NSCLC treatments, including radiotherapy, cytotoxic chemotherapies, targeted therapies, and emerging immunotherapies...
2018: International Journal of Biological Sciences
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