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WEE1 inhibitor

Jong Woo Lee, Janaki Parameswaran, Teresa Sandoval-Schaefer, Kyung Jin Eoh, Dong-Hua Yang, Fang Zhu, Ranee Mehra, Roshan Sharma, Stephen G Gaffney, Elizabeth B Perry, Jeffrey P Townsend, Ilya G Serebriiskii, Erica A Golemis, Natalia Issaeva, Wendell G Yarbrough, Ja Seok Koo, Barbara A Burtness
PURPOSE: Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in TP53, resulting in treatment resistance. In these patients, direct targeting of p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition...
February 12, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ji Hae Lee, Jee Young Sung, Eun Kyung Choi, Hyun-Kyoung Yoon, Bo Ram Kang, Eun Kyung Hong, Byung-Kiu Park, Yong-Nyun Kim, Seung Bae Rho, Kyungsil Yoon
The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates cellular proliferation, differentiation, apoptosis and tumorigenesis. Although the pro-oncogenic roles of C/EBPβ have been implicated in various human cancers, how it contributes to tumorigenesis or tumor progression has not been determined. Immunohistochemistry with human non-small cell lung cancer (NSCLC) tissues revealed that higher levels of C/EBPβ protein were expressed compared to normal lung tissues. Knockdown of C/EBPβ by siRNA reduced the proliferative capacity of NSCLC cells by delaying the G₂/M transition in the cell cycle...
February 11, 2019: Cells
Ahmed Diab, Micheal Kao, Keffy Kehrli, Hee Yeon Kim, Julia Sidorova, Eduardo Méndez
The p53 gene is the most commonly mutated gene in solid tumors but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a Phase I clinical trial. Here we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated...
January 24, 2019: Molecular Cancer Research: MCR
Amirali B Bukhari, Cody W Lewis, Joanna J Pearce, Deandra Luong, Gordon K Chan, Armin M Gamper
We used the cancer intrinsic property of oncogene-induced DNA damage as the base for a conditional synthetic lethality approach. To target mechanisms important for cancer cell adaptation to genotoxic stress and thereby to achieve cancer cell-specific killing, we combined inhibition of the kinases ATR and Wee1. Wee1 regulates cell cycle progression, whereas ATR is an apical kinase in the DNA damage response. In an orthotopic breast cancer model, tumor-selective synthetic lethality between bioavailable ATR and Wee1 inhibitors led to tumor remission and inhibited metastasis with minimal side effects...
January 15, 2019: Journal of Clinical Investigation
Sejin Chung, Paris J Vail, Agnieszka K Witkiewicz, Erik S Knudsen
PURPOSE: Cancer cells often have deficiencies in cell cycle control mechanisms and could be dependent on specific cell cycle checkpoints to maintain viability. Due to the documented role of KRAS in driving replication stress, we targeted the checkpoint governing DNA replication using CHK1 kinase inhibitors in pancreatic ductal adenocarcinoma (PDAC) models and examined mechanisms of resistance. EXPERIMENTAL DESIGN: Single agent efficacy of CHK1 inhibition was investigated in established and primary PDAC lines...
December 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Chi-Wai Cheng, Eric Tse
Cell cycle progression is tightly controlled by many cell cycle-regulatory proteins that are in turn regulated by a family of cyclin-dependent kinases (CDKs) through protein phosphorylation. The peptidyl-prolyl cis / trans isomerase PIN1 provides a further post-phosphorylation modification and functional regulation of these CDK-phosphorylated proteins. PIN1 specifically binds the phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif of its target proteins and catalyzes the cis / trans isomerization on the pSer/Thr-Pro peptide bonds...
2018: Frontiers in Pharmacology
Patrick G Pilié, Chad Tang, Gordon B Mills, Timothy A Yap
Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes...
October 24, 2018: Nature Reviews. Clinical Oncology
Brittany Haynes, Junko Murai, Jung-Min Lee
Poly(ADP-ribose) polymerase (PARP) inhibition serves as a potent therapeutic option eliciting synthetic lethality in cancers harboring homologous recombination (HR) repair defects, such as BRCA mutations. However, the development of resistance to PARP inhibitors (PARPis) poses a clinical challenge. Restoration of HR competency is one of the many molecular factors contributing to PARPi resistance. Combination therapy with cell cycle checkpoint (ATR, CHK1, and WEE1) inhibitors is being investigated clinically in many cancers, particularly in ovarian cancer, to enhance the efficacy and circumvent resistance to PARPis...
December 2018: Cancer Treatment Reviews
Hui-Ju Hsieh, Wei Zhang, Shu-Hong Lin, Wen-Hao Yang, Jun-Zhong Wang, Jianfeng Shen, Yiran Zhang, Yiling Lu, Hua Wang, Jane Yu, Gordon B Mills, Guang Peng
Checkpoint recovery, the process that checkpoint-arrested cells with normal DNA repair capacity resume cell cycle progression, is essential for genome stability. However, the signaling network of the process has not been clearly defined. Here, we combine functional proteomics, mathematical modeling, and molecular biology to identify mTORC1, the nutrient signaling integrator, as the determinant for G2/M checkpoint recovery. Inhibition of the mTORC1 pathway delays mitotic entry after DNA damage through KDM4B-mediated regulation of CCNB1 and PLK1 transcription...
September 28, 2018: Nature Communications
Albert Job, Lisa-Maria Schmitt, Lisa von Wenserski, Brigitte Lankat-Buttgereit, Thomas M Gress, Malte Buchholz, Eike Gallmeier
The phosphoinositide 3-kinase-related kinase ATR is a central regulator of the DNA damage response. Its chemical inhibition eliminates subsets of cancer cells in various tumor types. This effect is caused at least partly by the synthetically lethal relationship between ATR and certain DNA repair genes. In a previous screen using an siRNA library against DNA repair genes, we identified PRIM1, a part of the polymerase α-primase complex, as acting synthetically lethal with ATR. Applying a genetic ATR knock-in model of colorectal cancer cells, we confirmed that PRIM1 depletion inhibited proliferation of ATR-deficient cells and excluded artifacts due to clonal variation using an ATR reexpressing cell clone...
September 23, 2018: Neoplasia: An International Journal for Oncology Research
Yanchao Duan, Xin Dong, Jing Nie, Peng Li, Fei Lu, Daoxin Ma, Chunyan Ji
Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy affecting pediatric and adult populations. Although the outcomes of ALL in children have improved markedly in previous years, limited treatment strategies are available at present for adult patients with ALL. Wee1 is a crucial cell cycle checkpoint kinase of G2/M that regulates cell cycle progression and maintains chromatin integrity. MK-1775, a selective inhibitor of Wee1 has recently been identified to be able to induce apoptosis of tumor cells by abrogating G2/M checkpoint...
October 2018: Oncology Letters
Radoslaw Szmyd, Joanna Niska-Blakie, M Kasim Diril, Patrícia Renck Nunes, Konstantinos Tzelepis, Aurélie Lacroix, Noémi van Hul, Lih-Wen Deng, Joao Matos, Oliver Dreesen, Xavier Bisteau, Philipp Kaldis
Cell cycle regulation, especially faithful DNA replication and mitosis, are crucial to maintain genome stability. Cyclin-dependent kinase (CDK)/cyclin complexes drive most processes in cellular proliferation. In response to DNA damage, cell cycle surveillance mechanisms enable normal cells to arrest and undergo repair processes. Perturbations in genomic stability can lead to tumor development and suggest that cell cycle regulators could be effective targets in anticancer therapy. However, many clinical trials ended in failure due to off-target effects of the inhibitors used...
September 6, 2018: Oncogene
Yaping Li, Yinglan Pu, Hui Liu, Li Zhang, Xingyong Liu, Yan Li, Zhili Zuo
Wee1 plays a critical role in the arrest of G2/M cell cycle for DNA repair before entering mitosis. Many cancer cells have been identified as overexpression of Wee1. In this research, pharmacophore modeling, molecular docking and molecular dynamics simulation approaches were constructed to identify novel potential Wee1 inhibitors. A compound 8 was found to have a novel skeleton against Wee1 with an IC50 value of 22.32 µM and a Ki value of 13.11 µM. Kinetic assays were employed to evaluate the compound 8 as a competitive inhibitor...
September 2018: Journal of Computer-aided Molecular Design
Xian Chen, Kwang-Huei Low, Angela Alexander, Yufeng Jiang, Cansu Karakas, Kenneth R Hess, Jason P W Carey, Tuyen N Bui, Smruthi Vijayaraghavan, Kurt W Evans, Min Yi, D Christian Ellis, Kwok-Leung Cheung, Ian O Ellis, Siqing Fu, Funda Meric-Bernstam, Kelly K Hunt, Khandan Keyomarsi
Purpose: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. Experimental Design: Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles...
September 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Bin Fang, Aarthi Kannan, Tao Guo, Ling Gao
Purpose: Small cell lung cancer (SCLC) is highly lethal with no effective therapy. Wee1 kinase inhibitor AZD1775 (MK-1775) and mTOR kinase inhibitor MLN0128 (TAK228) are in clinical trials for relapsed SCLC and recurrent lung cancer, respectively. However, there is no preclinical data combining these two drugs in human cancers. Methods: In this study, we set to investigate the combinatorial anti-tumor effects of AZD1775 and MLN0128 on two human SCLC cell lines H69 and H82 in vitro and in vivo. Results: We have found that AZD1775 or MLN0128 treatment results in remarkably suppressed cell proliferation and increased cell death in vitro, what's more, the salient finding here is the potent anti-tumor effect observed in combinatorial treatment in H82 xenograft tumor...
2018: International Journal of Biological Sciences
Siqing Fu, Yudong Wang, Khandan Keyomarsi, Funda Meric-Bernstein
Wee1 kinase controls the G2-M checkpoint. Wee1 inhibition by AZD1775 allows cells with a deregulated G1 checkpoint to progress, resulting in catastrophe and apoptosis. The challenges ahead are in the establishment of the optimum dosing schedule either alone or in combination and the identification of patients with specific biomarker profiles who benefit most. Areas covered: This article provides an overview of AZD1775, based on English peer-reviewed articles on MEDLINE. The authors highlight the data from the published preclinical and clinical studies...
September 2018: Expert Opinion on Investigational Drugs
Subhayan Sur, Reina Sasaki, Pradip Devhare, Robert Steele, Ranjit Ray, Ratna B Ray
Chronic hepatitis C virus (HCV) infection may lead to end-stage liver disease, including hepatocellular carcinoma (HCC). We have shown previously that microRNA-373 (miR-373) is upregulated in HCV-infected human liver biopsy specimens. To gain insight into the role of miR-373 in HCV-mediated pathogenesis, we investigated its interacting partner for hepatocyte growth regulation. Transcriptome sequencing (RNA-seq) data revealed that Wee1 is associated with miR-373 and is a direct target. Interestingly, higher expression of Wee1 was noted in HCV-infected hepatocytes than in uninfected hepatocytes, suggesting that other factors may block miR-373-mediated Wee1 inhibition...
October 15, 2018: Journal of Virology
Yanqiu Hu, Lu Zhou, Xiaohong Zhu, Duoqian Dai, Yinfeng Bao, Yaping Qiu
Wee1-like protein kinase (Wee1) is a tyrosine kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Based on a series of signaling pathways initiated by Wee1, Wee1 has been recognized as a potential target for cancer therapy. In order to discover potent Wee1 inhibitors with novel scaffolds, ligand-based pharmacophore model has been built based on 101 known Wee1 inhibitors. Then the best pharmacophore model, AADRRR.340, with good PLS statistics (R2 = 0.9212, Q2 = 0...
July 27, 2018: Journal of Biomolecular Structure & Dynamics
Dongshao Chen, Xiaoting Lin, Jing Gao, Lin Shen, Zhongwu Li, Bin Dong, Cheng Zhang, Xiaotian Zhang
Based on the mechanisms by which Wee1 inhibitor and cisplatin played their own role, a promising strategy of Wee1 inhibitor combined with cisplatin was proposed, which was investigated in gastric cancer (GC). Either Wee1 inhibitor AZD1775 or cisplatin alone had a certain inhibitory effect on in vitro cell proliferation; however, the inhibitory effect was more significant when AZD1775 combined with cisplatin in vitro and in vivo . The underlying mechanisms unveiled that the increased DNA damage indicated by increased γ H2AX protein, as well as augmented cell apoptosis indicated by upregulated proapoptotic proteins, was responsible for the significant inhibitory effect of AZD1775 plus cisplatin...
2018: BioMed Research International
Xiaoting Lin, Dongshao Chen, Cheng Zhang, Xiaotian Zhang, Zhongwu Li, Bin Dong, Jing Gao, Lin Shen
BACKGROUND: Targeting poly ADP-ribose polymerase (PARP) has been recently identified as a promising option against gastric cancer (GC). However, PARP inhibitors alone achieve limited efficacy. Combination strategies, especially with homologous recombination (HR) impairment, are of great hope to optimize PARP inhibitor's efficacy and expand target populations but remains largely unknown. Herein, we investigated whether a WEE1/ Polo-like kinase 1 (PLK1) dual inhibitor AZD1775 reported to impair HR augmented anticancer activity of a PARP inhibitor olaparib and its underlying mechanisms...
June 28, 2018: Journal of Experimental & Clinical Cancer Research: CR
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