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https://www.readbyqxmd.com/read/28790110/replication-stress-leading-to-apoptosis-within-the-s-phase-contributes-to-synergism-between-vorinostat-and-azd1775-in-hnscc-harboring-high-risk-tp53-mutation
#1
Noriaki Tanaka, Ameeta A Patel, Lin Tang, Natalie L Silver, Antje Lindemann, Hideaki Takahashi, Roman Jaksik, Xiayu Rao, Nene N Kalu, Tseng-Cheng Chen, Jiping Wang, Mitchell J Frederick, Faye M Johnson, Frederico Gleber-Netto, Siqing Fu, Marek Kimmel, Jing Wang, Walter N Hittelman, Curtis R Pickering, Jeffrey N Myers, Abdullah A Osman
Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. Since mutation of TP53 in HNSCC occurs in 60-80% of non-HPV associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. <p>Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28706130/mutational-status-of-tp53-defines-the-efficacy-of-wee1-inhibitor-azd1775-in-kras-mutant-non-small-cell-lung-cancer
#2
Bo Mi Ku, Yeon-Hee Bae, Jiae Koh, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
KRAS is frequently mutated in non-small cell lung cancer (NSCLC). However, direct targeting of KRAS has proven to be challenging, and inhibition of KRAS effectors has resulted in limited clinical efficacy. Wee1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancers. Inhibition of Wee1 exerts anticancer effects as a monotherapy or in combination with DNA-damaging agents when cancer cells harbor TP53 mutations. However, its role in KRAS-mutant NSCLC, especially as a single agent, has not been explored...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28698200/targeting-axl-and-mtor-pathway-overcomes-primary-and-acquired-resistance-to-wee1-inhibition-in-small-cell-lung-cancer
#3
Triparna Sen, Pan Tong, Lixia Diao, Lerong Li, Youhong Fan, Jennifer Hoff, John Heymach, Jing Wang, Lauren A Byers
Purpose: Drugs targeting DNA repair and cell cycle checkpoints have emerged as promising therapies for small cell lung cancer (SCLC). Among these, the WEE1 inhibitor AZD1775 has shown clinical activity in a subset of SCLC patients, but resistance is common. Understanding primary and acquired resistance mechanisms will be critical for developing effective WEE1 inhibitor combinations. <p>Experimental Design: AZD1775 sensitivity in SCLC cell lines was correlated with baseline expression level of 200 total or phosphorylated proteins measured by reverse phase protein array (RPPA) to identify predictive markers of primary resistance...
July 11, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28663576/setd2-and-histone-h3-lysine-36-methylation-deficiency-in-advanced-systemic-mastocytosis
#4
G Martinelli, M Mancini, C De Benedittis, M Rondoni, C Papayannidis, M Manfrini, M Meggendorfer, R Calogero, V Guadagnuolo, M C Fontana, L Bavaro, A Padella, E Zago, L Pagano, R Zanotti, L Scaffidi, G Specchia, F Albano, S Merante, C Elena, P Savini, D Gangemi, P Tosi, F Ciceri, G Poletti, L Riccioni, F Morigi, M Delledonne, T Haferlach, M Cavo, P Valent, S Soverini
The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM...
June 16, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28655785/a-small-molecule-inhibitor-of-wee1-azd1775-synergizes-with-olaparib-by-impairing-homologous-recombination-and-enhancing-dna-damage-and-apoptosis-in-acute-leukemia
#5
Tamara B Garcia, Jonathan C Snedeker, Dmitry Baturin, Lori Gardner, Susan P Fosmire, Chengjing Zhou, Craig T Jordan, Sujatha Venkataraman, Rajeev Vibhakar, Christopher C Porter
Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies including cytarabine in AML and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine if AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this combination impaired proliferative capacity upon drug withdrawal...
June 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28652249/wee1-kinase-inhibitor-azd1775-has-preclinical-efficacy-in-lkb1-deficient-non-small-cell-lung-cancer
#6
Amanda L Richer, Jacqueline M Cala, Kelley O'Brien, Vashti M Carson, Landon J Inge, Timothy G Whitsett
G1-S checkpoint loss contributes to carcinogenesis and increases reliance upon the G2-M checkpoint for adaptation to stress and DNA repair, making G2-M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G2-M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several preclinical tumor models, often in the molecular context of TP53 loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28619757/cdk4-6-inhibitors-sensitize-rb-positive-sarcoma-cells-to-wee1-kinase-inhibition-through-reversible-cell-cycle-arrest
#7
Ashleigh M Francis, Angela Alexander, Yanna Liu, Smruthi Vijayaraghavan, Kwang Hui Low, Dong Yang, Tuyen Bui, Neeta Somaiah, Vinod Ravi, Khandan Keyomarsi, Kelly K Hunt
Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28557434/dual-targeting-of-wee1-and-plk1-by-azd1775-elicits-single-agent-cellular-anticancer-activity
#8
Gabriela Wright, Volha Golubeva, Lily L Remsing Rix, Norbert Berndt, Yunting Luo, Grace A Ward, Jhanelle E Gray, Ernst Schonbrunn, Harshani R Lawrence, Alvaro N A Monteiro, Uwe Rix
Inhibition of the WEE1 tyrosine kinase enhances anticancer chemotherapy efficacy. Accordingly, the WEE1 inhibitor AZD1775 (previously MK-1775) is currently under evaluation in clinical trials for cancer in combination with chemotherapy. AZD1775 has been reported to display high selectivity and is therefore used in many studies as a probe to interrogate WEE1 biology. However, AZD1775 also exhibits anticancer activity as a single agent although the underlying mechanism is not fully understood. Using a chemical proteomics approach, we here describe a proteome-wide survey of AZD1775 targets in lung cancer cells and identify several previously unknown targets in addition to WEE1...
July 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28442503/molecular-pathways-targeting-the-protein-kinase-wee1-in-cancer
#9
Jill J J Geenen, Jan H M Schellens
Wee1 is a protein kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDK) are a family of 14 serine/threonine protein kinases that coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G2 into mitosis. There are two mechanisms by which the G2 checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of the Wee1 kinase, which phosphorylates Cdc2. Blockade at the G2 checkpoint is especially important for p53-mutant cells because these tumors mainly rely on DNA repair at the G2 checkpoint...
August 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28296564/azd1775-induces-toxicity-through-double-stranded-dna-breaks-independently-of-chemotherapeutic-agents-in-p53-mutated-colorectal-cancer-cells
#10
Peter John Webster, Anna Tiffany Littlejohns, Hannah Jane Gaunt, K Raj Prasad, David John Beech, Dermot Anthony Burke
AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 μM to 3.5 μM...
March 15, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28208168/strategies-for-targeted-therapy-in-head-and-neck-squamous-cell-carcinoma-using-wee1-inhibitor-azd1775
#11
Michael Kao, Carlos Green, Julia Sidorova, Eduardo Méndez
No abstract text is available yet for this article.
June 1, 2017: JAMA Otolaryngology—Head & Neck Surgery
https://www.readbyqxmd.com/read/28178688/upregulated-wee1-protects-endothelial-cells-of-colorectal-cancer-liver-metastases
#12
Peter J Webster, Anna T Littlejohns, Hannah J Gaunt, Richard S Young, Baptiste Rode, Judith E Ritchie, Lucy F Stead, Sally Harrison, Alastair Droop, Heather L Martin, Darren C Tomlinson, Adam J Hyman, Hollie L Appleby, Sally Boxall, Alexander F Bruns, Jing Li, Raj K Prasad, J Peter A Lodge, Dermot A Burke, David J Beech
Surgical resection of colorectal cancer liver metastases (CLM) can be curative, yet 80% of patients are unsuitable for this treatment. As angiogenesis is a determinant of CLM progression we isolated endothelial cells from CLM and sought a mechanism which is upregulated, essential for angiogenic properties of these cells and relevant to emerging therapeutic options. Matched CLM endothelial cells (CLMECs) and endothelial cells of normal adjacent liver (LiECs) were superficially similar but transcriptome sequencing revealed molecular differences, one of which was unexpected upregulation and functional significance of the checkpoint kinase WEE1...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/27998224/phase-ii-study-of-wee1-inhibitor-azd1775-plus-carboplatin-in-patients-with-tp53-mutated-ovarian-cancer-refractory-or-resistant-to-first-line-therapy-within-3-months
#13
Suzanne Leijen, Robin M J M van Geel, Gabe S Sonke, Daphne de Jong, Efraim H Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Shelonitda Rose, Mark A Lee, Tomoko Freshwater, Jos H Beijnen, Jan H M Schellens
Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)-mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies...
December 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27939202/g2-checkpoint-targeting-and-radiosensitization-of-hpv-p16-positive-hnscc-cells-through-the-inhibition-of-chk1-and-wee1
#14
Chia-Jung Busch, Marie Sophie Kröger, Jana Jensen, Malte Kriegs, Fruzsina Gatzemeier, Cordula Petersen, Adrian Münscher, Kai Rothkamm, Thorsten Rieckmann
BACKGROUND AND PURPOSE: HPV-positive HNSCC cells are characterized by radiosensitivity, inefficient DNA double-strand break repair and a profound and prolonged arrest in G2. Here we explored the effect of clinically relevant inhibitors of Chk1 and Wee1 to inhibit the radiation-induced G2-arrest in order to achieve further radiosensitization. MATERIAL AND METHODS: Assessment of Chk1 activity by Western blot; assessment of cell cycle distribution by propidium iodide staining and flow cytometry; assessment of cell survival by colony formation assay...
February 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/27626672/drosophila-cancer-models-identify-functional-differences-between-ret-fusions
#15
Sarah Levinson, Ross L Cagan
We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities...
September 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27616351/wee1-inhibition-in-pancreatic-cancer-cells-is-dependent-on-dna-repair-status-in-a-context-dependent-manner
#16
Shruti Lal, Mahsa Zarei, Saswati N Chand, Emanuela Dylgjeri, Nicole C Mambelli-Lisboa, Michael J Pishvaian, Charles J Yeo, Jordan M Winter, Jonathan R Brody
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, in part, because of the lack of effective targeted therapeutic options. MK-1775 (also known as AZD1775), a mitotic inhibitor, has been demonstrated to enhance the anti-tumor effects of DNA damaging agents such as gemcitabine. We evaluated the efficacy of MK-1775 alone or in combination with DNA damaging agents (MMC or oxaliplatin) in PDA cell lines that are either DNA repair proficient (DDR-P) or deficient (DDR-D). PDA cell lines PL11, Hs 766T and Capan-1 harboring naturally selected mutations in DNA repair genes FANCC, FANCG and BRCA2 respectively, were less sensitive to MK-1775 as compared to two out of four representative DDR-P (MIA PaCa2 and PANC-1) cell lines...
September 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27601554/phase-i-study-evaluating-wee1-inhibitor-azd1775-as-monotherapy-and-in-combination-with-gemcitabine-cisplatin-or-carboplatin-in-patients-with-advanced-solid-tumors
#17
MULTICENTER STUDY
Suzanne Leijen, Robin M J M van Geel, Anna C Pavlick, Raoul Tibes, Lee Rosen, Albiruni R Abdul Razak, Raymond Lam, Tim Demuth, Shelonitda Rose, Mark A Lee, Tomoko Freshwater, Stuart Shumway, Li Wen Liang, Amit M Oza, Jan H M Schellens, Geoffrey I Shapiro
Purpose AZD1775 is a WEE1 kinase inhibitor targeting G2 checkpoint control, preferentially sensitizing TP53-deficient tumor cells to DNA damage. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of oral AZD1775 as monotherapy or in combination with chemotherapy in patients with refractory solid tumors. Patients and Methods In part 1, patients received a single dose of AZD1775 followed by 14 days of observation. In part 2, patients received AZD1775 as a single dose (part 2A) or as five twice per day doses or two once per day doses (part 2B) in combination with one of the following chemotherapy agents: gemcitabine (1,000 mg/m(2)), cisplatin (75 mg/m(2)), or carboplatin (area under the curve, 5 mg/mL⋅min)...
December 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27363019/targeting-the-wee1-kinase-as-a-molecular-targeted-therapy-for-gastric-cancer
#18
Hye-Young Kim, Yunhee Cho, HyeokGu Kang, Ye-Seal Yim, Seok-Jun Kim, Jaewhan Song, Kyung-Hee Chun
Wee1 is a member of the Serine/Threonine protein kinase family and is a key regulator of cell cycle progression. It has been known that WEE1 is highly expressed and has oncogenic functions in various cancers, but it is not yet studied in gastric cancers. In this study, we investigated the oncogenic role and therapeutic potency of targeting WEE1 in gastric cancer. At first, higher expression levels of WEE1 with lower survival probability were determined in stage 4 gastric cancer patients or male patients with accompanied lymph node metastasis...
August 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27324022/identification-of-clinically-achievable-combination-therapies-in-childhood-rhabdomyosarcoma
#19
COMPARATIVE STUDY
Elliot Kahen, Diana Yu, Douglas J Harrison, Justine Clark, Pooja Hingorani, Christopher L Cubitt, Damon R Reed
PURPOSE: Systemic therapy has improved rhabdomyosarcoma event-free and overall survival; however, approximately 40 % of patients will have progressive or recurrent disease which is difficult to cure and remains a considerable challenge. Minimal progress has been made in improving outcomes for metastatic or relapsed RMS due to a lack of effective therapeutic agents. Targeted therapies are likely to be incorporated into regimens which rely on conventional cytotoxic chemotherapy. A system to evaluate novel combinations of interest is needed...
August 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27318641/an-aqueous-normal-phase-chromatography-coupled-with-tandem-mass-spectrometry-method-for-determining-unbound-brain-to-plasma-concentration-ratio-of-azd1775-a-wee1-kinase-inhibitor-in-patients-with-glioblastoma
#20
Jianmei Wu, Nader Sanai, Xun Bao, Patricia LoRusso, Jing Li
A rapid, sensitive, and robust aqueous normal-phase chromatography method coupled with tandem mass spectrometry was developed and validated for the quantitation of AZD1775, a Wee-1 inhibitor, in human plasma and brain tumor tissue. Sample preparation involved simple protein precipitation with acetonitrile. Chromatographic separation was achieved on ethylene bridged hybrid stationary phases (i.e., Waters XBridge Amide column) under an isocratic elution with the mobile phase consisting of acetonitrile/ammonium formate in water (10mM, pH 3...
August 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
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