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https://www.readbyqxmd.com/read/28088511/brief-report-egfr-l858m-l861q-cis-mutations-confer-selective-sensitivity-to-afatinib
#1
Jamie A Saxon, Lynette M Sholl, Pasi A Jänne
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with epidermal growth factor receptor (EGFR)-mutant lung cancers. However, the therapeutic efficacy of TKIs in patients with uncommon EGFR mutations remains unclear. METHODS: Next-generation sequencing was performed on a patient's lung adenocarcinoma tumor sample, revealing rare combined in cis (on the same allele) EGFR mutations. Stable Ba/F3 and NIH-3T3 cell lines harboring the mutations were established to investigate the effect of first, second, and third generation EGFR TKIs on cell proliferation by MTS assay and EGFR phosphorylation by Western blotting...
January 11, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28079885/mirna182-regulates-percentage-of-myeloid-and-erythroid-cells-in-chronic-myeloid-leukemia
#2
Deepak Arya, Sasikala P Sachithanandan, Cecil Ross, Dasaradhi Palakodeti, Shang Li, Sudhir Krishna
The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr-Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28077790/flt3-activating-mutations-display-differential-sensitivity-to-multiple-tyrosine-kinase-inhibitors
#3
Bao Nguyen, Allen B Williams, David J Young, Hayley Ma, Li Li, Mark Levis, Patrick Brown, Donald Small
Fms-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that normally functions in hematopoietic cell survival, proliferation and differentiation. Constitutively activating mutations of FLT3 map predominately to the juxtamembrane domain (internal tandem duplications; ITD) or the activation loop (AL) of the kinase domain and are detected in about 1/3 of de novo acute myeloid leukemia (AML) patients. Small molecule tyrosine kinase inhibitors (TKI) effectively target FLT3/ITD mutations, but some activating mutations, particularly those on the AL, are relatively resistant to many FLT3 TKI...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28073786/phase-1-study-of-twice-weekly-pulse-dose-and-daily-low-dose-erlotinib-as-initial-treatment-for-patients-with-egfr-mutant-lung-cancers
#4
H A Yu, C Sima, D Feldman, L L Liu, B Vaitheesvaran, J Cross, C M Rudin, M G Kris, W Pao, F Michor, G J Riely
BACKGROUND: Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control. METHODS: We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib...
October 25, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28068944/the-acceleration-of-glucose-accumulation-in-renal-cell-carcinoma-assessed-by-fdg-pet-ct-demonstrated-acquisition-of-resistance-to-tyrosine-kinase-inhibitor-therapy
#5
Noboru Nakaigawa, Keiichi Kondo, Daiki Ueno, Kazuhiro Namura, Kazuhide Makiyama, Kazuki Kobayashi, Koichi Shioi, Ichiro Ikeda, Takeshi Kishida, Tomohiro Kaneta, Ryogo Minamimoto, Ukihide Tateishi, Tomio Inoue, Masahiro Yao
BACKGROUND: Tyrosine-kinase inhibitor (TKI) targeting angiogenesis improves the prognosis of patients with metastatic renal cell carcinoma (RCC), but its effect is temporary. In order to understand the mechanism by which RCC acquires resistance to TKI, we investigated the change of glucose accumulation in RCC by FDG PET/CT when they demonstrated progression disease (PD) against TKI. METHODS: We monitored the FDG accumulation in RCC of 38 patients treated with TKI by 162 PET/CT sequentially until they were judged to demonstrate PD...
January 9, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28068878/long-term-control-of-hypercortisolism-by-vandetanib-in-a-medullary-thyroid-carcinoma-with-a-somatic-ret-mutation
#6
Anne-Cécile Paepegaey, Beatrix Cochand-Priollet, Estelle Louiset, Pierre Olivier Sarfati, Marco Alifano, Nelly Burnichon, Marie Bienvenu-Perrard, Najiba Lahlou, Léopoldine Bricaire, Lionel Groussin
CONTEXT: Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome have a poor prognosis, partially due to the difficulties to control hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an antisecretory action on ACTH. However, there is a lack of long-term follow-up studies. CASE DESCRIPTION: We report the case of a 58 year-old man with a MTC-related Cushing's syndrome resistant to a combination of several anticortisolic drugs...
January 9, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28061471/transformation-to-small-cell-carcinoma-as-an-acquired-resistance-mechanism-to-azd9291-a-case-report
#7
Lin Li, Hui Wang, Chao Li, Zheng Wang, Ping Zhang, Xu Yan
AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months' treatment of AZD9291 with hepatic metastasis...
January 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28050230/givinostat-a-type-ii-histone-deacetylase-inhibitor-induces-potent-caspase-dependent-apoptosis-in-human-lymphoblastic-leukemia
#8
Ying Li, Kevin Zhao, Chenjiao Yao, Samir Kahwash, Yan Tang, Guojiuan Zhang, Kara Patterson, Qi-En Wang, Weiqiang Zhao
Unlike chronic myeloid leukemia, patients with acute lymphoblastic leukemia (ALL) with Philadelphia chromosome (Ph+) do not respond well to Imatinib or tyrosine kinase inhibitors (TKI). In addition, TKI might induce resistant mutations in kinase domain (KD) of ABL in patients with relapsed diseases. Of the histone deacetylase (HDAC) inhibitors, suberoylanilide hydroxamic acid (SAHA) has shown to induce potent cytotoxicity on acute myeloid leukemia cell lines but Givinostat effect on acute lymphoblastic leukemia (ALL) has not been reported...
September 2016: Genes & Cancer
https://www.readbyqxmd.com/read/28040594/transcriptome-analysis-of-egfr-tyrosine-kinase-inhibitors-resistance-associated-long-noncoding-rna-in-non-small-cell-lung-cancer
#9
Pei Ma, Meiling Zhang, Fengqi Nie, Zebo Huang, Jing He, Wei Li, Liang Han
The non-small cell lung cancer (NSCLC) patients harbor mutations in the epidermal growth factor receptor (EGFR) can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib, and show improved progression-free survival. However, most of the patients who are initially responsive to EGFR TKIs with activating EGFR mutations eventually develop acquired resistance after long-term therapy, and are followed by disease progression. Recently, diverse mechanisms of acquired EGFR TKI resistance have been reported, but little is known about the role of long noncoding RNAs in EGFR TKIs resistance...
December 29, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28024692/synchronous-occurrence-of-squamous-cell-carcinoma-transformation-and-egfr-exon-20-s768i-mutation-as-a-novel-mechanism-of-resistance-in-egfr-mutated-lung-adenocarcinoma
#10
Lucia Longo, Maria Cecilia Mengoli, Federica Bertolini, Stefania Bettelli, Samantha Manfredini, Giulio Rossi
The occurrence of secondary EGFR mutation T790M in exon 20 and histologic "transformation" are common mechanisms underlying resistance to EGFR first- or second-generation tyrosine kinase inhibitors (TKI). We describe here on a hitherto unreported mechanism of EGFR TKI resistance synchronously combining squamous-cell carcinoma change and occurrence of the EGFR exon 20 S768I secondary mutation in a 43 year-old woman with stage IV adenocarcinoma harbouring EGFR exon 21 L858R mutation. After 8 months of response to gefitinib, the patient experienced EGFR TKI resistance and died of leptomeningeal neoplastic dissemination...
January 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28024517/-role-of-bone-marrow-mesenchymal-stem-cells-in-resistance-of-chronic-myeloid-leukemia-to-tyrosine-kinase-inhibitors-review
#11
Xiao-Yan Zhang, Qian Wan, Li-Jun Fang, Jian Li
Chronic myeloid leukemia (CML) is a disease originated from malignant hematopoietic stem cell disorder. In CML, mesenchymal stem cells(MSC) have been changed in the bone marrow microenvironment, which can protect the leukemia cells from apoptosis induced by tyrosine kinase inhibitors (TKI) and lead to the resistance to TKI by the secretion of soluble factors, involvement in cell-cell adhesion, and so on. This review mainly focuses on the changes of the bone marrow mesenchymal stem cells in CML, as well as the role and mechanism of MSC in the CML resistance of TKI...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
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-tki
#12
Sabine Schmid, Oliver Gautschi, Sacha Rothschild, Michael Mark, Patrizia Froesch, Dirk Klingbiel, Hermann Reichegger, Wolfram Jochum, Joachim Diebold, Früh Martin
BACKGROUND: Non-small cell lung cancer (NSCLC) with de novo anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations co-occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients (pts) are poorly understood. METHODS: Outcomes of pts with metastatic NSCLC de novo co- alterations of ALK/EGFR or ALK/KRAS detected by FISH (ALK) and sequencing (EGFR/KRAS) from six Swiss centres were analysed...
December 19, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28003335/the-ras-related-gtpase-rhob-confers-resistance-to-egfr-tyrosine-kinase-inhibitors-in-non-small-cell-lung-cancer-via-an-akt-dependent-mechanism
#13
Olivier Calvayrac, Julien Mazières, Sarah Figarol, Claire Marty-Detraves, Isabelle Raymond-Letron, Emilie Bousquet, Magali Farella, Estelle Clermont-Taranchon, Julie Milia, Isabelle Rouquette, Nicolas Guibert, Amélie Lusque, Jacques Cadranel, Nathalie Mathiot, Ariel Savina, Anne Pradines, Gilles Favre
Although lung cancer patients harboring EGFR mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI), most of them rapidly relapse. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR-TKI In a series of samples from EGFR-mutated patients, we found that low RHOB expression correlated with a good response to EGFR-TKI treatment while a poor response correlated with high RHOB expression (15...
December 21, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28002980/targeting-the-egfr-t790m-mutation-in-non-small-cell-lung-cancer
#14
Nicola Normanno, Monica Rosaria Maiello, Nicoletta Chicchinelli, Alessia Iannaccone, Claudia Esposito, Rossella De Cecio, Amelia D'alessio, Antonella De Luca
The presence of activating mutations of the epidermal growth factor receptor (EGFR) is predictive of response to first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC). However, patients that initially respond to these drugs inexorably become resistant. The T790M mutation in the exon 20 of the EGFR is the main mechanism of resistance to EGFR TKIs occurring in over 50% of the cases. Third generation EGFR TKIs have been shown to be active in patients who progressed after TKI treatment and carry the T790M mutation...
December 23, 2016: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28002337/anti-cd19-chimeric-antigen-receptor-t-cell-therapy-for-adult-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-two-case-reports
#15
Yang-Min Zhu, Zhao Wu, You-Ping Tan, Yuan-Yuan Du, Zhi Liu, Rui-Ming Ou, Shuang Liu, Cheng-Fei Pu, Jing Jiang, Jin-Ping Wang, Lei Xiao, Qing Zhang
RATIONALE: The presence of the Philadelphia chromosome (Ph) in acute lymphoblastic leukemia (ALL) has been associated with a high risk of disease relapse and a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for adults with Ph-positive ALL, but relapse remains the primary cause of treatment failure, and is associated with an extremely poor prognosis. The emergence of resistance to tyrosine kinase inhibitors (TKIs) poses a challenge for patients with disease relapses after initial treatment with TKI-containing regimens...
December 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28000387/a-comparison-of-ddpcr-and-arms-for-detecting-egfr-t790m-status-in-ctdna-from-advanced-nsclc-patients-with%C3%A2-acquired-egfr-tki-resistance
#16
Wenxian Wang, Zhengbo Song, Yiping Zhang
A sensitive and convenient method for detecting epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance would be desirable to direct patient sequential treatment strategy. A comparison of two platforms for detecting EGFR mutations in plasma ctDNA was undertaken. Plasma samples and tumor samples were collected from patients with acquired EGFR-TKI resistance in Zhejiang Cancer Hospital from December 2014 to December 2015...
December 20, 2016: Cancer Medicine
https://www.readbyqxmd.com/read/27999193/the-novel-anticancer-agent-jnj-26854165-is-active-in-chronic-myeloid-leukemic-cells-with-unmutated-bcr-abl-and-t315i-mutant-bcr-abl-through-promoting-proteosomal-degradation-of-bcr-abl-proteins
#17
Liangshun You, Hui Liu, Jian Huang, Wanzhuo Xie, Jueying Wei, Xiujin Ye, Wenbin Qian
Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53-dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant...
December 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27992557/an-analysis-of-egfr-mutations-among-1506-cases-of-non-small-cell-lung-cancer-patients-in-guangxi-china
#18
Wen-E Wei, Nai-Quan Mao, Shu-Fang Ning, Ji-Lin Li, Hai-Zhou Liu, Tong Xie, Jian-Hong Zhong, Yan Feng, Chang-Hong Wei, Li-Tu Zhang
An association between epidermal growth factor receptor (EGFR) and clinical characteristics of non-small cell lung cancer (NSCLC) was reported ten years ago. In addition, a different type of relationship was seen in different ethic races. However, the relationship between these factors is not well understood in the Guangxi province. Up to now, there are only very limited data on the association of TTF1/EGFR protein positivity and EGFR mutation status in NSCLC. This study aims to investigate the role of EGFR gene mutation status on the clinical characteristics and the relationship with TTF-1/EGFR protein positivity of patients with NSCLC in Guangxi, China...
2016: PloS One
https://www.readbyqxmd.com/read/27989877/chinese-herbal-medicine-fuzheng-kang-ai-decoction-sensitized-the-effect-of-gefitinib-on-inhibition-of-human-lung-cancer-cells-through-inactivating-pi3-k-akt-mediated-suppressing-muc1-expression
#19
Longmei Li, SuMei Wang, Fang Zheng, WanYin Wu, Swei Sunny Hann
ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) Fuzheng Kang-Ai (FZKA for short) decoction has been used as adjuvant treatment strategies in lung cancer patients for decades. However, the molecular mechanism underlying the therapeutic potential especially in sensitizing the effect of EGFR-TKI gefitinib has not been well elucidated. MATERIALS AND METHODS: Cell viability was detected by MTT assay. Cell cycle distribution was detected by flow cytometry...
October 28, 2016: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/27987579/response-and-acquired-resistance-to-crizotinib-in-chinese-patients-with-lung-adenocarcinomas-harboring-met-exon-14-splicing-alternations
#20
Hua-Jie Dong, Peng Li, Chang-Ling Wu, Xiao-Yue Zhou, Hong-Jun Lu, Tong Zhou
Approximately 10% of lung adenocarcinomas harbor aberrations that are targetable using the approved multitargeted TKI crizotinib. MET exon 14 skipping mutation predicts for response to crizotinib in human lung adenocarcinomas. However, a substantial part of patients still has no sufficient tissue to perform genomic analysis. As a promising noninvasive biomarker and potential surrogate for the entire tumor genome, circulating tumor DNA (ctDNA) has been applied to the detection of driver gene mutations. Here we described the MET exon 14 splicing mutations in cell-free circulating-tumor DNA by next-generation sequencing (NGS) technology...
December 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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