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https://www.readbyqxmd.com/read/29614485/mir-99a-enhances-the-radiation-sensitivity-of-non-small-cell-lung-cancer-by-targeting-mtor
#1
Hang Yin, Jianqun Ma, Lin Chen, Shiqi Piao, Yu Zhang, Siliang Zhang, Hongyu Ma, Yang Li, Yuanyuan Qu, Xiaoyuan Wang, Qingyong Xu
BACKGROUND/AIMS: Radiation therapy is an important and effective modality for the treatment of non-small cell lung cancer (NSCLC). MicroRNAs (miRNAs) are crucial post-transcriptional regulators that are involved in numerous important biologic processes. However, their potential involvement in radiation sensitivity remains unknown. MATERIALS: We performed integrated analysis of miRNA expression in NSCLC using The Cancer Genome Atlas datasets. miR-99a was found to be significantly upregulated in cancer tissue and regulated cell survival...
March 26, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29496664/in-vivo-e2f-reporting-reveals-efficacious-schedules-of-mek1-2-cdk4-6-targeting-and-mtor-s6-resistance-mechanisms
#2
Jessica L F Teh, Phil F Cheng, Timothy J Purwin, Neda Nikbakht, Prem Patel, Inna Chervoneva, Adam Ertel, Paolo M Fortina, Ines Kleiber, Kim HooKim, Michael A Davies, Lawrence N Kwong, Mitch P Levesque, Reinhard Dummer, Andrew E Aplin
Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein...
March 1, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29487712/inhibition-of-mtorc1-c2-signaling-improves-anti-leukemia-efficacy-of-jak-stat-blockade-in-crlf2-rearranged-and-or-jak-driven-philadelphia-chromosome-like-acute-b-cell-lymphoblastic-leukemia
#3
Qi Zhang, Ce Shi, Lina Han, Nitin Jain, Kathryn G Roberts, Helen Ma, Tianyu Cai, Antonio Cavazos, Yoko Tabe, Rodrigo O Jacamo, Hong Mu, Yang Zhao, Jing Wang, Shuo-Chieh Wu, Fenglin Cao, Zhihong Zeng, Jin Zhou, Yingchang Mi, Elias J Jabbour, Ross Levine, Sarah K Tasian, Charles G Mullighan, David M Weinstock, David A Fruman, Marina Konopleva
Patients with cytokine receptor-like factor 2 rearranged ( CRLF2 -re) subgroup Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like B-ALL) have a high relapse rate and poor clinical outcomes. CRFL2 -re Ph-like B-ALL is characterized by heightened activation of multiple signaling pathways, including the JAK/STAT and PI3K/AKT/mTOR pathways. We hypothesized that the combined inhibition by JAK2 and mTOR inhibitors would induce an additive antileukemia effect in CRLF2 -re Ph-like B-ALL. In this study, we tested the antileukemia efficacy of the type I JAK inhibitor ruxolitinib and type II JAK inhibitor NVP-BBT594 (hereafter abbreviated BBT594) [1] alone and combined with allosteric mTOR inhibitor rapamycin and a second generation ATP-competitive mTOR kinase inhibitor AZD2014...
January 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29389967/raptor-up-regulation-contributes-to-resistance-of-renal-cancer-cells-to-pi3k-mtor-inhibition
#4
Philip Earwaker, Caroline Anderson, Frances Willenbrock, Adrian L Harris, Andrew S Protheroe, Valentine M Macaulay
The outlook for patients with advanced renal cell cancer (RCC) has been improved by targeted agents including inhibitors of the PI3 kinase (PI3K)-AKT-mTOR axis, although treatment resistance is a major problem. Here, we aimed to understand how RCC cells acquire resistance to PI3K-mTOR inhibition. We used the RCC4 cell line to generate a model of in vitro resistance by continuous culture in PI3K-mTOR kinase inhibitor NVP-BEZ235 (BEZ235, Dactolisib). Resistant cells were cross-resistant to mTOR inhibitor AZD2014...
2018: PloS One
https://www.readbyqxmd.com/read/29371953/evaluation-of-the-combination-of-the-dual-m-torc1-2-inhibitor-vistusertib-azd2014-and-paclitaxel-in-ovarian-cancer-models
#5
Anne-Christine Wong Te Fong, Parames Thavasu, Sladjana Gagrica, Karen E Swales, Martin O Leach, Sabina C Cosulich, Yuen-Li Chung, Udai Banerji
Activation of the PI3K/mTOR pathway has been shown to be correlated with resistance to chemotherapy in ovarian cancer. We aimed to investigate the effects of combining inhibition of mTORC1 and 2 using the mTOR kinase inhibitor vistusertib (AZD2014) with paclitaxel in in vitro and in vivo ovarian cancer models. The combination of vistusertib and paclitaxel on cell growth was additive in a majority of cell lines in the panel ( n = 12) studied. A cisplatin- resistant model (A2780Cis) was studied in vitro and in vivo ...
December 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207163/preclinical-analysis-of-mtor-complex-1-2-inhibition-in-diffuse-intrinsic-pontine-glioma
#6
Patrick C Flannery, John A DeSisto, Vladimir Amani, Sujatha Venkataraman, Rakeb T Lemma, Eric W Prince, Andrew Donson, Erin E Moroze, Lindsey Hoffman, Jean M Mulcahy Levy, Nicholas Foreman, Rajeev Vibhakar, Adam L Green
Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brain tumor. The mechanistic target of rapamycin (MTOR), a key oncogene, functions as two distinct signaling complexes, MTORC1 and MTORC2. We set out to determine the preclinical efficacy and mechanism of action of MTOR inhibitors in DIPG. We evaluated the MTORC1 inhibitor everolimus and the MTORC1/2 inhibitor AZD2014 in three patient-derived DIPG cell lines using cell culture models. We created dose-response curves for both compounds. We measured phenotypic effects on cell self-renewal, apoptosis, cell cycle, differentiation, senescence, and autophagy...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/28885497/influence-of-the-novel-atp-competitive-dual-mtorc1-2-inhibitor-azd2014-on-immune-cell-populations-and-heart-allograft-rejection
#7
Daniel Fantus, Helong Dai, Yoshihiro Ono, Alicia Watson, Shinichiro Yokota, Kanishka Mohib, Osamu Yoshida, Mark A Ross, Simon C Watkins, Bala Ramaswami, Anna Valusjkikh, David M Rothstein, Angus W Thomson
BACKGROUND: Little is known about how new-generation adenosine triphosphate-competitive mechanistic target of rapamycin (mTOR) kinase inhibitors affect immunity and allograft rejection. METHODS: mTOR complex (C) 1 and 2 signaling in dendritic cells and T cells was analyzed by Western blotting, whereas immune cell populations in normal and heart allograft recipient mice were analyzed by flow cytometry. Alloreactive T cell proliferation was quantified in mixed leukocyte reaction; intracellular cytokine production and serum antidonor IgG levels were determined by flow analysis and immunofluorescence staining used to detect IgG in allografts...
December 2017: Transplantation
https://www.readbyqxmd.com/read/28664293/targeting-autophagy-to-modulate-cell-survival-a-comparative-analysis-in-cancer-normal-and-embryonic-cells
#8
COMPARATIVE STUDY
Aleksandra Divac Rankov, Mila Ljujić, Marija Petrić, Dragica Radojković, Milica Pešić, Jelena Dinić
Autophagy is linked to multiple cancer-related signaling pathways, and represents a defense mechanism for cancer cells under therapeutic stress. The crosstalk between apoptosis and autophagy is essential for both tumorigenesis and embryonic development. We studied the influence of autophagy on cell survival in pro-apoptotic conditions induced by anticancer drugs in three model systems: human cancer cells (NCI-H460, COR-L23 and U87), human normal cells (HaCaT and MRC-5) and zebrafish embryos (Danio rerio). Autophagy induction with AZD2014 and tamoxifen antagonized the pro-apoptotic effect of chemotherapeutics doxorubicin and cisplatin in cell lines, while autophagy inhibition by wortmannin and chloroquine synergized the action of both anticancer agents...
November 2017: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/28028034/rapamycin-insensitive-companion-of-mtor-rictor-amplification-defines-a-subset-of-advanced-gastric-cancer-and-is-sensitive-to-azd2014-mediated-mtorc1-2-inhibition
#9
S T Kim, S Y Kim, S J Klempner, J Yoon, N Kim, S Ahn, H Bang, K-M Kim, W Park, S H Park, J O Park, Y S Park, H Y Lim, S H Lee, K Park, W K Kang, J Lee
Background: Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed. Patients and methods: Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets...
March 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27863413/rictor-amplification-identifies-a-subgroup-in-small-cell-lung-cancer-and-predicts-response-to-drugs-targeting-mtor
#10
Nneha Sakre, Gary Wildey, Mohadese Behtaj, Adam Kresak, Michael Yang, Pingfu Fu, Afshin Dowlati
Small cell lung cancer (SCLC) is an aggressive cancer that represents ~15% of all lung cancers. Currently there are no targeted therapies to treat SCLC. Our genomic analysis of a metastatic SCLC cohort identified recurrent RICTOR amplification. Here, we examine the translational potential of this observation. RICTOR was the most frequently amplified gene observed (~14% patients), and co-amplified with FGF10 and IL7R on chromosome 5p13. RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/27441499/insights-into-significance-of-combined-inhibition-of-mek-and-m-tor-signalling-output-in-kras-mutant-non-small-cell-lung-cancer
#11
Sophie Broutin, Adam Stewart, Parames Thavasu, Angelo Paci, Jean-Michel Bidart, Udai Banerji
BACKGROUND: We aimed to understand the dependence of MEK and m-TOR inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cell lines. METHODS: In a panel of KRAS(M) and KRAS(WT) NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively. RESULTS: GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, P<10(-4))...
August 23, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/27399333/overproduction-of-igf-2-drives-a-subset-of-colorectal-cancer-cells-which-specifically-respond-to-an-anti-igf-therapeutic-antibody-and-combination-therapies
#12
H Zhong, C Fazenbaker, C Chen, S Breen, J Huang, X Yao, P Ren, Y Yao, R Herbst, R E Hollingsworth
Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody...
February 9, 2017: Oncogene
https://www.readbyqxmd.com/read/27267837/bez235-pik3-mtor-inhibitor-overcomes-pazopanib-resistance-in-patient-derived-refractory-soft-tissue-sarcoma-cells
#13
Hee Kyung Kim, Sun Young Kim, Su Jin Lee, Mihyeon Kang, Seung Tae Kim, Jiryeon Jang, Oliver Rath, Julia Schueler, Dong Woo Lee, Woong Yang Park, Sung Joo Kim, Se Hoon Park, Jeeyun Lee
BACKGROUND: Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients...
June 2016: Translational Oncology
https://www.readbyqxmd.com/read/27031247/azd2014-radiosensitizes-oral-squamous-cell-carcinoma-by-inhibiting-akt-mtor-axis-and-inducing-g1-g2-m-cell-cycle-arrest
#14
Chih-Chia Yu, Hsien-bin Huang, Shih-Kai Hung, Hui-Fen Liao, Ching-Chih Lee, Hon-Yi Lin, Szu-Chin Li, Hsu-Chueh Ho, Chung-Lin Hung, Yu-Chieh Su
BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common malignant neoplasms in Taiwan. Activation of the mTOR signaling pathway has been linked to decreased radiation responsiveness in human oral cancer, thus it limits efficacy of radiotherapy. To address this question, we investigated the effect of AZD2014, a novel small molecular ATP-competitive inhibitor of mTORC1 and mTORC2 kinase, as a radiosensitizer in primary OSCC and OSCC-derived cell line models. METHODS: We isolated primary tumor cells from OSCC tissues and cell lines...
2016: PloS One
https://www.readbyqxmd.com/read/26989080/identification-of-differential-pi3k-pathway-target-dependencies-in-t-cell-acute-lymphoblastic-leukemia-through-a-large-cancer-cell-panel-screen
#15
James T Lynch, Robert McEwen, Claire Crafter, Ultan McDermott, Mathew J Garnett, Simon T Barry, Barry R Davies
Selective phosphoinositide 3-kinase (PI3K)/AKT/mTOR inhibitors are currently under evaluation in clinical studies. To identify tumor types that are sensitive to PI3K pathway inhibitors we screened compounds targeting PI3Kα/δ (AZD8835), PI3Kβ/δ (AZD8186), AKT (AZD5363) and mTORC1/2 (AZD2014) against a cancer cell line panel (971 cell lines). There was an enrichment of hematological malignancies that were sensitive to AKT and mTOR inhibition, with the greatest degree of sensitivity observed in T-cell acute lymphoblastic leukemia (T-ALL)...
April 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/26978006/long-term-acquired-everolimus-resistance-in-pancreatic-neuroendocrine-tumours-can-be-overcome-with-novel-pi3k-akt-mtor-inhibitors
#16
Timon Vandamme, Matthias Beyens, Ken Op de Beeck, Fadime Dogan, Peter M van Koetsveld, Patrick Pauwels, Geert Mortier, Christel Vangestel, Wouter de Herder, Guy Van Camp, Marc Peeters, Leo J Hofland
BACKGROUND: The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described. METHODS: QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 μM everolimus, respectively, 1000-fold and 250-fold initial IC50. Using total DNA content as a measure of cell number, growth inhibitory dose-response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal...
March 15, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/26473447/the-novel-combination-of-dual-mtor-inhibitor-azd2014-and-pan-pim-inhibitor-azd1208-inhibits-growth-in-acute-myeloid-leukemia-via-hsf-pathway-suppression
#17
Masako Harada, Juliana Benito, Shinichi Yamamoto, Surinder Kaur, Dirim Arslan, Santiago Ramirez, Rodrigo Jacamo, Leonidas Platanias, Hiromichi Matsushita, Tsutomu Fujimura, Saiko Kazuno, Kensuke Kojima, Yoko Tabe, Marina Konopleva
Mammalian target of rapamycin (mTOR) signaling is a critical pathway in the biology of acute myeloid leukemia (AML). Proviral integration site for moloney murine leukemia virus (PIM) serine/threonine kinase signaling takes part in various pathways exerting tumorigenic properties. We hypothesized that the combination of a PIM kinase inhibitor with an mTOR inhibitor might have complementary growth-inhibitory effects against AML. The simultaneous inhibition of the PIM kinase by pan-PIM inhibitor AZD1208 and of mTOR by selective mTORC1/2 dual inhibitor AZD2014 exerted anticancer properties in AML cell lines and in cells derived from primary AML samples with or without supportive stromal cell co-culture, leading to suppressed proliferation and increased apoptosis...
November 10, 2015: Oncotarget
https://www.readbyqxmd.com/read/26364551/a-randomised-phase-2-study-of-azd2014-versus-everolimus-in-patients-with-vegf-refractory-metastatic-clear-cell-renal-cancer
#18
RANDOMIZED CONTROLLED TRIAL
Thomas Powles, Matthew Wheater, Omar Din, Thomas Geldart, Ekaterini Boleti, Andrew Stockdale, Santhanam Sundar, Angus Robinson, Imtiaz Ahmed, Akhila Wimalasingham, Wendy Burke, Shah-Jalal Sarker, Syed Hussain, Christy Ralph
BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). OBJECTIVE: The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC...
March 2016: European Urology
https://www.readbyqxmd.com/read/26359452/kinome-rnai-screens-reveal-synergistic-targeting-of-mtor-and-fgfr1-pathways-for-treatment-of-lung-cancer-and-hnscc
#19
Katherine R Singleton, Trista K Hinz, Emily K Kleczko, Lindsay A Marek, Jeff Kwak, Taylor Harp, Jihye Kim, Aik Choon Tan, Lynn E Heasley
The FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of selective tyrosine kinase inhibitors (TKI) are underway. Treatment with a single TKI represents a logical step toward personalized cancer therapy, but intrinsic and acquired resistance mechanisms limit their long-term benefit. In this study, we deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and head and neck squamous cell cancer (HNSCC) cells to ponatinib, a multikinase FGFR-active inhibitor...
October 15, 2015: Cancer Research
https://www.readbyqxmd.com/read/26358751/azd2014-an-inhibitor-of-mtorc1-and-mtorc2-is-highly-effective-in-er-breast-cancer-when-administered-using-intermittent-or-continuous-schedules
#20
Sylvie M Guichard, Jon Curwen, Teeru Bihani, Celina M D'Cruz, James W T Yates, Michael Grondine, Zoe Howard, Barry R Davies, Graham Bigley, Teresa Klinowska, Kurt G Pike, Martin Pass, Christine M Chresta, Urszula M Polanska, Robert McEwen, Oona Delpuech, Stephen Green, Sabina C Cosulich
mTOR is an atypical serine threonine kinase involved in regulating major cellular functions, such as nutrients sensing, growth, and proliferation. mTOR is part of the multiprotein complexes mTORC1 and mTORC2, which have been shown to play critical yet functionally distinct roles in the regulation of cellular processes. Current clinical mTOR inhibitors only inhibit the mTORC1 complex and are derivatives of the macrolide rapamycin (rapalogs). Encouraging effects have been observed with rapalogs in estrogen receptor-positive (ER(+)) breast cancer patients in combination with endocrine therapy, such as aromatase inhibitors...
November 2015: Molecular Cancer Therapeutics
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