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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
Michael Kao, Carlos Green, Julia Sidorova, Eduardo Méndez
No abstract text is available yet for this article.
February 16, 2017: JAMA Otolaryngology—Head & Neck Surgery
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...
February 2, 2017: Oncotarget
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
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...
December 8, 2016: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
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
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
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
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
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
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
Christopher J Matheson, Sujatha Venkataraman, Vladimir Amani, Peter S Harris, Donald S Backos, Andrew M Donson, Michael F Wempe, Nicholas K Foreman, Rajeev Vibhakar, Philip Reigan
No abstract text is available yet for this article.
July 15, 2016: ACS Chemical Biology
Ankita Jhuraney, Nicholas T Woods, Gabriela Wright, Lily Rix, Fumi Kinose, Jodi L Kroeger, Elizabeth Remily-Wood, W Douglas Cress, John M Koomen, Stephen G Brantley, Jhanelle E Gray, Eric B Haura, Uwe Rix, Alvaro N Monteiro
The DNA damage response (DDR) involves a complex network of signaling events mediated by modular protein domains such as the BRCA1 C-terminal (BRCT) domain. Thus, proteins that interact with BRCT domains and are a part of the DDR constitute potential targets for sensitization to DNA-damaging chemotherapy agents. We performed a pharmacologic screen to evaluate 17 kinases, identified in a BRCT-mediated interaction network as targets to enhance platinum-based chemotherapy in lung cancer. Inhibition of mitotic kinase WEE1 was found to have the most effective response in combination with platinum compounds in lung cancer cell lines...
July 2016: Molecular Cancer Therapeutics
Jennifer O'Neil, Yair Benita, Igor Feldman, Melissa Chenard, Brian Roberts, Yaping Liu, Jing Li, Astrid Kral, Serguei Lejnine, Andrey Loboda, William Arthur, Razvan Cristescu, Brian B Haines, Christopher Winter, Theresa Zhang, Andrew Bloecher, Stuart D Shumway
Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic drug combinations can convert weakly efficacious monotherapies into regimens that produce robust antitumor activity. This can be explained in part through pathway interdependencies that are critical for cancer cell proliferation and survival. However, identification of the various interdependencies is difficult due to the complex molecular circuitry that underlies tumor development and progression...
June 2016: Molecular Cancer Therapeutics
Kyle C Cuneo, Meredith A Morgan, Mary A Davis, Leslie A Parcels, Joshua Parcels, David Karnak, Caila Ryan, Na Liu, Jonathan Maybaum, Theodore S Lawrence
PURPOSE: Wee1 kinase inhibitors are effective radiosensitizers in cells lacking a G1 checkpoint. In this study we examined the potential effect of Wee1 kinase inhibition on inducing replication stress in hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Five independent datasets from the Oncomine database comparing gene expression in HCC compared to normal tissue were combined and specific markers associated with Wee1 sensitivity were analyzed. We then performed a series of in vitro experiments to study the effect of Wee1 inhibition on irradiated HCC cell lines with varying p53 mutational status...
June 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Sophia X Pfister, Enni Markkanen, Yanyan Jiang, Sovan Sarkar, Mick Woodcock, Giulia Orlando, Ioanna Mavrommati, Chen-Chun Pai, Lykourgos-Panagiotis Zalmas, Neele Drobnitzky, Grigory L Dianov, Clare Verrill, Valentine M Macaulay, Songmin Ying, Nicholas B La Thangue, Vincenzo D'Angiolella, Anderson J Ryan, Timothy C Humphrey
Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a synthetic lethal interaction in which H3K36me3-deficient cancers are acutely sensitive to WEE1 inhibition. We show that RRM2, a ribonucleotide reductase subunit, is the target of this synthetic lethal interaction. RRM2 is regulated by two pathways here: first, H3K36me3 facilitates RRM2 expression through transcription initiation factor recruitment; second, WEE1 inhibition degrades RRM2 through untimely CDK activation...
November 9, 2015: Cancer Cell
Tasneem Kausar, Jason S Schreiber, David Karnak, Leslie A Parsels, Joshua D Parsels, Mary A Davis, Lili Zhao, Jonathan Maybaum, Theodore S Lawrence, Meredith A Morgan
To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR) repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by γH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively...
October 2015: Neoplasia: An International Journal for Oncology Research
James B Ford, Dmitry Baturin, Tamara M Burleson, Annemie A Van Linden, Yong-Mi Kim, Christopher C Porter
While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis...
September 29, 2015: Oncotarget
Khanh Do, Deborah Wilsker, Jiuping Ji, Jennifer Zlott, Tomoko Freshwater, Robert J Kinders, Jerry Collins, Alice P Chen, James H Doroshow, Shivaani Kummar
PURPOSE: Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies...
October 20, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
L Zhou, Y Zhang, S Chen, M Kmieciak, Y Leng, H Lin, K A Rizzo, C I Dumur, A Ferreira-Gonzalez, Y Dai, S Grant
AZD1775 targets the cell cycle checkpoint kinase Wee1 and potentiates genotoxic agent cytotoxicity through p53-dependent or -independent mechanisms. Here, we report that AZD1775 interacted synergistically with histone deacetylase inhibitors (HDACIs, for example, Vorinostat), which interrupt the DNA damage response, to kill p53-wild type (wt) or -deficient as well as FLT3-ITD leukemia cells in association with pronounced Wee1 inhibition and diminished cdc2/Cdk1 Y15 phosphorylation. Similarly, Wee1 shRNA knockdown significantly sensitized cells to HDACIs...
April 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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