Gene Summary

Gene:WEE1; WEE1 G2 checkpoint kinase
Aliases: WEE1A, WEE1hu
Summary:This gene encodes a nuclear protein, which is a tyrosine kinase belonging to the Ser/Thr family of protein kinases. This protein catalyzes the inhibitory tyrosine phosphorylation of CDC2/cyclin B kinase, and appears to coordinate the transition between DNA replication and mitosis by protecting the nucleus from cytoplasmically activated CDC2 kinase. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:wee1-like protein kinase
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (22)
Pathways:What pathways are this gene/protein implicaed in?
Show (4)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer Gene Expression Regulation
  • Pyrazoles
  • Cell Cycle Checkpoints
  • ras-GRF1
  • cdc25 Phosphatases
  • Transcription
  • Cell Cycle Proteins
  • Spindle Apparatus
  • Prostate Cancer
  • MicroRNAs
  • Down-Regulation
  • Western Blotting
  • Nasopharyngeal Cancer
  • G2 Phase Cell Cycle Checkpoints
  • Drug Synergism
  • Antineoplastic Agents
  • Protein-Tyrosine Kinases
  • Cell Cycle
  • Chromosome 11
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Mutation
  • Protein Kinases
  • Breast Cancer
  • Mitosis
  • Molecular Targeted Therapy
  • Apoptosis
  • Sequence Deletion
  • DNA Damage
  • Cyclin-Dependent Kinases
  • Protein Kinase Inhibitors
  • Phosphorylation
  • RNA Interference
  • Cell Proliferation
  • Tyrosine
  • DNA Repair
  • Nuclear Proteins
  • Gene Expression Profiling
  • CDC2 Protein Kinase
  • Checkpoint Kinase 1
  • Drug Resistance
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: WEE1 (cancer-related)

Shaabanpour Aghamaleki F, Mollashahi B, Aghamohammadi N, et al.
Bioinformatics Analysis of Key Genes and Pathways for Medulloblastoma as a Therapeutic Target
Asian Pac J Cancer Prev. 2019; 20(1):221-227 [PubMed] Free Access to Full Article Related Publications
Introduction: One of the major challenges in cancer treatment is the lack of specific and accurate treatment in cancer. Data analysis can help to understand the underlying molecular mechanism that leads to better treatment. Increasing availability and reliability of DNA microarray data leads to increase the use of these data in a variety of cancers. This study aimed at applying and evaluating microarray data analyzing, identification of important pathways and gene network for medulloblastoma patients to improve treatment approaches especially target therapy. Methods: In the current study, Microarray gene expression data (GSE50161) were extracted from Geo datasets and then analyzed by the affylmGUI package to predict and investigate upregulated and downregulated genes in medulloblastoma. Then, the important pathways were determined by using software and gene enrichment analyses. Pathways visualization and network analyses were performed by Cytoscape. Results: A total number of 249 differentially expressed genes (DEGs) were identified in medulloblastoma compared to normal samples. Cell cycle, p53, and FoxO signaling pathways were indicated in medulloblastoma, and CDK1, CCNB1, CDK2, and WEE1 were identified as some of the important genes in the medulloblastoma. Conclusion: Identification of critical and specific pathway in any disease, in our case medulloblastoma, can lead us to better clinical management and accurate treatment and target therapy.

Chen X, Zhang N
Downregulation of lncRNA NEAT1_2 radiosensitizes hepatocellular carcinoma cells through regulation of miR-101-3p/WEE1 axis.
Cell Biol Int. 2019; 43(1):44-55 [PubMed] Related Publications
Radioresistance is a major obstacle in hepatocellular carcinoma (HCC) radiotherapy. Aberrant expression of long non-coding RNA (lncRNA) has been postulated to be implicated in the development of HCC radioresistance. We investigated the role of lncRNA nuclear enriched abundant transcript 1_2 (NEAT1_2) in radioresistance of HCC and its molecular mechanism in this study. We found that NEAT1_2 and WEE1 were upregulated, and miR-101-3p was downregulated in HCC tissues, as well as HCC cell lines. Downregulation of WEE1 sensitized the radiosensitivity of HCC cells, as evidenced by decreased survival fractions of Huh7 and PLC5 cells and increased percentage of apoptotic cells. Also, knockdown of NEAT1_2 exerted a reinforcing effect on the radiosensitivity of HCC cells. In addition, WEE1 was confirmed as a direct target of miR-101-3p. Upregulation of miR-101-3p obviously decreased the mRNA and protein levels of WEE1 compared with that in the miR-NC group, while transfection of anta-miR-101-3p presented the opposite effects. In parallel, NEAT1_2 was identified to interact with miR-101-3p, and NEAT1_2 upregulated the expression of WEE1 in Huh7 cells through sponging miR-101-3p. Besides, the reinforcing effect of NEAT1_2 silencing could be attenuated by downregulation of miR-101-3p. To conclude, our results support the concept that downregulation of lncRNA NEAT1_2 radiosensitizes hepatocellular carcinoma cells through regulation of miR-101-3p/WEE1 axis.

Jain A, Brown SZ, Thomsett HL, et al.
Evaluation of Post-transcriptional Gene Regulation in Pancreatic Cancer Cells: Studying RNA Binding Proteins and Their mRNA Targets.
Methods Mol Biol. 2019; 1882:239-252 [PubMed] Related Publications
Post-transcriptional regulation of gene expression through interaction between RNA binding proteins (RBPs) and target mRNAs have gained considerable interest over the last decade. Altered expression of RBPs as detected in pancreatic ductal adenocarcinoma (PDAC) cells alters mRNA processing, and in turn, the entire transcriptome and proteome. Thus, this gene regulatory mechanism can regulate important pro-oncogenic signaling pathways (e.g., TP53, WEE1, and c-MYC) in PDAC cells. Ribonucleoprotein immunoprecipitation assays (RNP-IP or RIP) are a modified immunoprecipitation method to study physical interactions between RBPs and their mRNA targets. As a first step to explore RBP interactomes and define novel therapeutic targets and dysregulated pathways in disease, RIPs are a sensitive and established molecular biology technique used to isolate and differentiate bound transcripts to RBPs in a variety of experimental conditions. This chapter describes an up-to-date, detailed protocol for performing this assay in mammalian cytoplasmic extracts (i.e., PDAC cells), and reviews current methods to validate target binding sites such as electrophoretic mobility shift assay (EMSA) and cross-linking immunoprecipitation polymerase chain reaction (CLIP-PCR).

Pilié PG, Tang C, Mills GB, Yap TA
State-of-the-art strategies for targeting the DNA damage response in cancer.
Nat Rev Clin Oncol. 2019; 16(2):81-104 [PubMed] Related Publications
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. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.

Qian W, Zhang Z, Peng W, et al.
CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer.
Int J Oncol. 2018; 53(5):2021-2033 [PubMed] Free Access to Full Article Related Publications
Dysregulated cell cycle progression serves a crucial role in tumor development. Cell division cycle-associated 3 (CDCA3) is considered a trigger of mitotic entry; it is an important part of the S phase kinase-associated protein 1/Cullin/F-box ubiquitin ligase complex and mediates the destruction of mitosis-inhibitory kinase wee1. However, little is known about the role of CDCA3 in cancer, particularly colorectal cancer (CRC). The present study aimed to explore the biological and clinical significance of CDCA3 in CRC growth and progression. CDCA3 expression was significantly associated with tumor progression and poor survival. Overexpression of CDCA3 increased proliferation in LoVo CRC cells, whereas CDCA3 knockdown in SW480 CRC cells led to decreased proliferation, in vitro and in vivo. Further mechanistic investigations demonstrated that reduced CDCA3 expression resulted in G1/S phase transition arrest, which was attributed to a significant accumulation of p21 in SW480 cells; conversely, increased CDCA3 expression promoted G1/S phase transition through decreased p21 accumulation in LoVo cells. It was also demonstrated that CDCA3 was able to regulate the expression of transcription factor E2F1, thereby repressing p21 expression. Taken together, these results suggested that overexpression of CDCA3 may serve a crucial role in tumor malignant potential and that CDCA3 may be used as a prognostic factor and a potential therapeutic target in CRC.

Stewart E, McEvoy J, Wang H, et al.
Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses.
Cancer Cell. 2018; 34(3):411-426.e19 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Personalized cancer therapy targeting somatic mutations in patient tumors is increasingly being incorporated into practice. Other therapeutic vulnerabilities resulting from changes in gene expression due to tumor specific epigenetic perturbations are progressively being recognized. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. We integrated transcriptomic, epigenomic, and proteomic/phosphoproteomic data to elucidate the cellular origins and therapeutic vulnerabilities of rhabdomyosarcoma (RMS). We discovered that alveolar RMS occurs further along the developmental program than embryonal RMS. We also identified deregulation of the RAS/MEK/ERK/CDK4/6, G

Zhang W, Lu Y, Li X, et al.
CDCA3 promotes cell proliferation by activating the NF-κB/cyclin D1 signaling pathway in colorectal cancer.
Biochem Biophys Res Commun. 2018; 500(2):196-203 [PubMed] Related Publications
Cell division cycle associated 3 (CDCA3) is required for mitotic entry, and mediates the degradation of the inhibitory kinase Wee1. New evidence suggests CDCA3 plays a role in tumor promotion. However, little is known about the relevance of CDCA3 in colorectal cancer(CRC), especially in the regulation of NF-κB activity. In this study, we found that colorectal tumors significantly expressed more CDCA3 than non-cancer tissues. In addition, CDCA3 promoted CRC cell proliferation in vitro. Furthermore, downregulation of CDCA3 not only induced cell cycle arrest but also facilitated apoptosis. Mechanistically, CDCA3 activates the NF-κB signaling pathway by interacting with TRAF2 in CRC. Together, these results define a tumor-supportive role for CDCA3, which may also provide a new promising strategy for treating CRC.

Jiaranuchart S, Kaida A, Onozato Y, et al.
DNA damage response following X-irradiation in oral cancer cell lines HSC3 and HSC4.
Arch Oral Biol. 2018; 90:1-8 [PubMed] Related Publications
OBJECTIVE: The objective of this study was to characterize the DNA damage response in two human oral cancer cell lines following X-irradiation.
DESIGN: To visualize radiation-induced cell cycle alterations, two human oral cancer cell lines, HSC3 and HSC4, expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) were established in this study. G2 arrest kinetics following irradiation were obtained from two-color flow cytometric analysis and pedigrees of Fucci fluorescence. DNA double strand break repair kinetics were obtained from immunofluorescence staining for phosphorylated histone H2AX, p53-binding protein 1, phosphorylated DNA-dependent protein kinase catalytic subunit, and breast cancer susceptibility gene 1.
RESULTS: Both cell lines showed apparent G2 arrest after 10 Gy of irradiation, but it was more enhanced in the HSC3-Fucci cells. Radiosensitivity was higher in the HSC3-Fucci cells than in HSC4-Fucci cells. Pedigree analysis of Fucci fluorescence revealed that the HSC3-Fucci cells exhibited a significantly longer green phase (normally indicating S/G2/M phases, but here reflective of G2 arrest) when irradiated in the red phase (G1 phase) than HSC4-Fucci cells irradiated in either red or green phases. Non-homologous end joining was marginally suppressed during the G1 phase and markedly more likely to be impaired during the S/G2 phases in HSC3-Fucci cells. When G2 arrest was abrogated by checkpoint kinase 1 or Wee1 inhibitors, only HSC4-Fucci cells exhibited radiosensitization.
CONCLUSIONS: We characterized DNA damage response in HSC3-Fucci and HSC4-Fucci cells following irradiation and the former demonstrated inefficient non-homologous end joining, especially during the S/G2 phases, resulting in enhanced G2 arrest. These findings may have clinical implications for oral cancer.

Shu C, Wang Q, Yan X, Wang J
Whole-Genome Expression Microarray Combined with Machine Learning to Identify Prognostic Biomarkers for High-Grade Glioma.
J Mol Neurosci. 2018; 64(4):491-500 [PubMed] Related Publications
The aim of our study is to build a framework for a better understanding of high-grade glioma (HGG) prognostic-related biomarkers. Whole-genome gene expression microarray was performed to identify differently expressed genes between HGGs and low-grade diffuse gliomas. Several machine learning algorithms were used to filter prognostic-related genes. One hundred ninety-three HGG patients after surgical resection were selected for survival analysis. Immunohistochemistry were performed on these tumor samples to analyze IDH1 mutation status and protein expression of WEE1. qRT-PCR, western blotting, transwell assays, and scratch wound healing assays were performed to evaluate the effect of WEE1 knockdown or overexpression in HGG cells. Three prognostic-related genes (WEE1, IGF2PB3, and EMP3) were demonstrated to separate HGG patients into two different survival subgroups. The area under receiver operating characteristic curve of WEE1 was higher than that of IGF2BP3, EMP3, age, IDH status, 1p/19q status, and MGMT promoter status. WEE1 was an independent covariate compared with IDH status, age, and WHO grade. Knockdown or overexpression of WEE1 can inhibit or promote migration and invasion in U251 and U87 cell lines. WEE1, EMP3, and IGF2BP3 are reliable prognostic-related genes at the mRNA level. WEE1 is an independent prognostic biomarker in survival analysis and has potential diagnostic value for HGG patients. WEE1 can induce HGG cell migration and invasion in vitro.

de Jong MRW, Visser L, Huls G, et al.
Identification of relevant drugable targets in diffuse large B-cell lymphoma using a genome-wide unbiased CD20 guilt-by association approach.
PLoS One. 2018; 13(2):e0193098 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Forty percent of patients with diffuse large B-cell lymphoma (DLBCL) show resistant disease to standard chemotherapy (CHOP) in combination with the anti-CD20 monoclonal antibody rituximab (R). Although many new anti-cancer drugs were developed in the last years, it is unclear which of these drugs can be safely combined to improve standard therapy without antagonizing anti-CD20 efficacy. In this study, we aimed to identify rituximab compatible drug-target combinations for DLBCL. For this, we collected gene expression profiles of 1,804 DLBCL patient samples. Subsequently, we performed a guilt-by-association analysis with MS4A1 (CD20) and prioritized the 500 top-ranked CD20-associated gene probes for drug-target interactions. This analysis showed the well-known genes involved in DLBCL pathobiology, but also revealed several genes that are relatively unknown in DLBCL, such as WEE1 and PARP1. To demonstrate potential clinical relevance of these targets, we confirmed high protein expression of WEE1 and PARP1 in patient samples. Using clinically approved WEE1 and PARP1 inhibiting drugs in combination with rituximab, we demonstrated significantly improved DLBCL cell killing, also in rituximab-insensitive cell lines. In conclusion, as exemplified by WEE1 and PARP1, our CD20-based genome-wide analysis can be used as an approach to identify biological relevant drug-targets that are rituximab compatible and may be implemented in phase 1/2 clinical trials to improve DLBCL treatment.

Lindemann A, Takahashi H, Patel AA, et al.
Targeting the DNA Damage Response in OSCC with TP53 Mutations.
J Dent Res. 2018; 97(6):635-644 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer worldwide and in the United States. OSCC remains a major cause of morbidity and mortality in patients with head and neck cancers. Tobacco and alcohol consumption alone or with chewing betel nut are potential risk factors contributing to the high prevalence of OSCC. Multimodality therapies, including surgery, chemotherapy, biologic therapy, and radiotherapy, particularly intensity-modulated radiotherapy (IMRT), are the current treatments for OSCC patients. Despite recent advances in these treatment modalities, the overall survival remains poor over the past years. Recent data from whole-exome sequencing reveal that TP53 is commonly mutated in human papillomavirus-negative OSCC patients. Furthermore, these data stressed the importance of the TP53 gene in suppressing the development and progression of OSCC. Clinically, TP53 mutations are largely associated with poor survival and tumor resistance to radiotherapy and chemotherapy in OSCC patients, which makes the TP53 mutation status a potentially useful molecular marker prognostic and predictive of clinical response in these patients. Several forms of DNA damage have been shown to activate p53, including those generated by ionizing radiation and chemotherapy. The DNA damage stabilizes p53 in part via the DNA damage signaling pathway that involves sensor kinases, including ATM and ATR and effector kinases, such as Chk1/2 and Wee1, which leads to posttranscriptional regulation of a variety of genes involved in DNA repair, cell cycle control, apoptosis, and senescence. Here, we discuss the link of TP53 mutations with treatment outcome and survival in OSCC patients. We also provide evidence that small-molecule inhibitors of critical proteins that regulate DNA damage repair and replication stress during the cell cycle progression, as well as other molecules that restore wild-type p53 activity to mutant p53, can be exploited as novel therapeutic approaches for the treatment of OSCC patients bearing p53 mutant tumors.

Caiola E, Frapolli R, Tomanelli M, et al.
Wee1 inhibitor MK1775 sensitizes KRAS mutated NSCLC cells to sorafenib.
Sci Rep. 2018; 8(1):948 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Non-Small-Cell Lung Cancer (NSCLC) is a poorly chemosensitive tumor and targeted therapies are only used for about 15% of patients where a specific driving and druggable lesion is observed (EGFR, ALK, ROS). KRAS is one of the most frequently mutated genes in NSCLC and patients harboring these mutations do not benefit from specific treatments. Sorafenib, a multi-target tyrosine kinase inhibitor, was proposed as a potentially active drug in KRAS-mutated NSCLC patients, but clinical trials results were not conclusive. Here we show that the NSCLC cells' response to sorafenib depends on the type of KRAS mutation. KRAS G12V cells respond less to sorafenib than the wild-type counterpart, in vitro and in vivo. To overcome this resistance, we used high-throughput screening with a siRNA library directed against 719 human kinases, and Wee1 was selected as a sorafenib response modulator. Inhibition of Wee1 by its specific inhibitor MK1775 in combination with sorafenib restored the KRAS mutated cells' response to the multi-target tyrosine kinase inhibitor. This combination of the Wee1 inhibitor with sorafenib, if confirmed in models with different genetic backgrounds, might be worth investigating further as a new strategy for KRAS mutated NSCLC.

Karakashev S, Zhu H, Yokoyama Y, et al.
BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer.
Cell Rep. 2017; 21(12):3398-3405 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers.

Dinavahi SS, Noory MA, Gowda R, et al.
Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations.
Mol Pharmacol. 2018; 93(3):190-196 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino-

Schmidt M, Rohe A, Platzer C, et al.
Regulation of G2/M Transition by Inhibition of WEE1 and PKMYT1 Kinases.
Molecules. 2017; 22(12) [PubMed] Article available free on PMC after 10/09/2019 Related Publications
In the cell cycle, there are two checkpoint arrests that allow cells to repair damaged DNA in order to maintain genomic integrity. Many cancer cells have defective G1 checkpoint mechanisms, thus depending on the G2 checkpoint far more than normal cells. G2 checkpoint abrogation is therefore a promising concept to preferably damage cancerous cells over normal cells. The main factor influencing the decision to enter mitosis is a complex composed of Cdk1 and cyclin B. Cdk1/CycB is regulated by various feedback mechanisms, in particular inhibitory phosphorylations at Thr14 and Tyr15 of Cdk1. In fact, Cdk1/CycB activity is restricted by the balance between WEE family kinases and Cdc25 phosphatases. The WEE kinase family consists of three proteins: WEE1, PKMYT1, and the less important WEE1B. WEE1 exclusively mediates phosphorylation at Tyr15, whereas PKMYT1 is dual-specific for Tyr15 as well as Thr14. Inhibition by a small molecule inhibitor is therefore proposed to be a promising option since WEE kinases bind Cdk1, altering equilibria and thus affecting G2/M transition.

Ma H, Lian R, Wu Z, et al.
MiR-503 enhances the radiosensitivity of laryngeal carcinoma cells via the inhibition of WEE1.
Tumour Biol. 2017; 39(10):1010428317706224 [PubMed] Related Publications
Enhancing the sensitivity of laryngeal cells to radiation is crucial for improving the efficacy of laryngeal carcinoma. MicroRNAs are known to play a major role in regulating cellular radiosensitivity. This study was designed to explore the effect and the molecular basis of miR-503 in the radiosensitivity of laryngeal carcinoma cells. Quantitative real-time polymerase chain reaction analysis showed that miR-503 expression was decreased in human laryngeal carcinoma cell lines Hep-2 and TU212, and the downregulation of miR-503 was also observed after irradiation. Upregulation of miR-503 by pre-miR-503 transfection restrained proliferation, promoted progression of Hep-2 and TU212 cells through the cell cycle after irradiation, and sensitized cells to radiation. Dual-Luciferase Reporter Assay verified a direct interaction between miR-503 and the WEE1 messenger RNA 3'-untranslated region. The overexpression of miR-503 significantly decreased WEE1 expression at the messenger RNA and protein levels, whereas the inhibition of miR-503 upregulated the expression of WEE1. WEE1 knockdown by WEE1 small interfering RNA apparently abrogated the inhibitory effect of anti-miR-503 on radiosensitivity. In conclusion, miR-503 could function as an enhancer of radiation responses in laryngeal carcinoma cells by inhibiting WEE1, which may be a potential novel radiosensitizing strategy for laryngeal carcinoma.

Wu S, Wang S, Gao F, et al.
Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma.
Neuro Oncol. 2018; 20(1):78-91 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Background: Oncogenic activation of phosphatidylinositol-3 kinase (PI3K) signaling plays a pivotal role in the development of glioblastoma (GBM). However, pharmacological inhibition of PI3K has so far not been therapeutically successful due to adaptive resistance through a rapid rewiring of cancer cell signaling. Here we identified that WEE1 is activated after transient exposure to PI3K inhibition and confers resistance to PI3K inhibition in GBM.
Methods: Patient-derived glioma-initiating cells and established GBM cells were treated with PI3K inhibitor or WEE1 inhibitor alone or in combination, and cell proliferation was evaluated by CellTiter-Blue assay. Cell apoptosis was analyzed by TUNEL, annexin V staining, and blotting of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. Both subcutaneous xenograft and orthotropic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis; the tumor growth was monitored by bioluminescence imaging, and tumor tissue was analyzed by immunohistochemistry to validate signaling changes.
Results: PI3K inhibition activates WEE1 kinase, which in turn phosphorylates cell division control protein 2 homolog (Cdc2) at Tyr15 and inhibits Cdc2 activity, leading to G2/M arrest in a p53-independent manner. WEE1 inhibition abrogated the G2/M arrest and propelled cells to prematurely enter into mitosis and consequent cell death through mitotic catastrophe and apoptosis. Additionally, combination treatment significantly suppressed tumor growth in a subcutaneous model but not in an intracranial model due to limited blood-brain barrier penetration.
Conclusions: Our findings highlight WEE1 as an adaptive resistant gene activated after PI3K inhibition, and inhibition of WEE1 potentiated the effectiveness of PI3K targeted inhibition, suggesting that a combinational inhibition of WEE1 and PI3K might allow successful targeted therapy in GBM.

Brandsma I, Fleuren EDG, Williamson CT, Lord CJ
Directing the use of DDR kinase inhibitors in cancer treatment.
Expert Opin Investig Drugs. 2017; 26(12):1341-1355 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
INTRODUCTION: Defects in the DNA damage response (DDR) drive the development of cancer by fostering DNA mutation but also provide cancer-specific vulnerabilities that can be exploited therapeutically. The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1. Areas covered: We summarise the current stage of development of these novel DDR kinase inhibitors, and describe which predictive biomarkers might be exploited to direct their clinical use. Expert opinion: Novel DDR inhibitors present promising candidates in cancer treatment and have the potential to elicit synthetic lethal effects. In order to fully exploit their potential and maximize their utility, identifying highly penetrant predictive biomarkers of single agent and combinatorial DDR inhibitor sensitivity are critical. Identifying the optimal drug combination regimens that could used with DDR inhibitors is also a key objective.

Li J, Wu J, Bao X, et al.
Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients Using an IVIVE-PBPK Modeling Approach.
Clin Cancer Res. 2017; 23(24):7454-7466 [PubMed] Article available free on PMC after 10/09/2019 Related Publications

Stewart E, Federico SM, Chen X, et al.
Orthotopic patient-derived xenografts of paediatric solid tumours.
Nature. 2017; 549(7670):96-100 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.

Kuzu OF, Gowda R, Sharma A, et al.
Identification of WEE1 as a target to make AKT inhibition more effective in melanoma.
Cancer Biol Ther. 2018; 19(1):53-62 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
AKT3 is one of the major therapeutic targets in melanoma but clinically targeting AKT3 alone seems to be an ineffective therapeutic approach. To identify unique strategies to enhance the efficacy of targeting AKT3, a screen was undertaken where AKT3 was co-targeted with a panel of kinases important in melanoma development. The screen identified WEE1 as the most potent target that when inhibited along with AKT3 would enhance the efficacy of targeting AKT3 in melanoma. RNAi mediated inhibition of AKT3 and WEE1 synergistically inhibited the viability of melanoma cells leading to a 65-75% decrease in tumor development. This approach was effective by mechanistically modulating pathways associated with the transcription factors p53 and FOXM1. Simultaneously regulating the activity of these two transcriptionally driven pathways, cooperatively deregulated cell cycle control and DNA damage repair to synergistically kill melanoma cells. This study uniquely identifies a potential approach to improve the efficacy of targeting AKT3 in melanoma.

Tong S, Si Y, Yu H, et al.
MLN4924 (Pevonedistat), a protein neddylation inhibitor, suppresses proliferation and migration of human clear cell renal cell carcinoma.
Sci Rep. 2017; 7(1):5599 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Neddylation is a post-translational protein modification associated with cancer development. MLN4924 is a neddylation inhibitor currently under investigation in multiple phase I studies on various malignancies, and its clincal name is Pevonedistat. It has been documented that MLN4924 blocks Cullins neddylation and inactivates CRLs and, in turn, triggers cell-cycle arrest, apoptosis, senescence and autophagy in many cancer cells. In this study, we investigated the anti-tumor effect of MLN4924 in human clear cell renal carcinoma (ccRCC). Levels of both Nedd8 activating enzyme E1 and Nedd8-conjugating enzyme E2 were higher in ccRCC tissues and RCC cancer cells than in normal. Moreover, MLN4924 treatment led to rapid inhibition of Cullin1 neddylation and notably suppressed growth and survival as well as migration in a dose-and time-dependent manner. Mechanistic studies revealed that MLN4924 induced the accumulation of a number of CRL substrates, including p21, p27 and Wee1 to trigger DNA damage and induce growth arrest at the G2/M phase. MLN4924 also induced anti-migration and anti-invasion by activating E-cadherin and repressing Vimentin. Taken together, this study provides the first evidence that neddylation pathway is overactive in ccRCC and that MLN4924 induces dose-dependent anti-proliferation, anti-migration, anti-invasion in ccRCC cells. The study thus indicates that MLN4924 has potential therapeutic value for the clinical treatment of renal cancer.

Sen T, Tong P, Diao L, et al.
Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer.
Clin Cancer Res. 2017; 23(20):6239-6253 [PubMed] Article available free on PMC after 10/09/2019 Related Publications

Richer AL, Cala JM, O'Brien K, et al.
WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non-Small Cell Lung Cancer.
Cancer Res. 2017; 77(17):4663-4672 [PubMed] Related Publications

Francis AM, Alexander A, Liu Y, et al.
CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest.
Mol Cancer Ther. 2017; 16(9):1751-1764 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
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 (>5 cm), 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. Here we describe the development of a synergistic combination treatment strategy that may be applicable in both soft tissue sarcomas as well as sarcomas of bone that takes advantage of targeting the cell cycle. We show that Rb-positive cell lines treated with the CDK4/6 inhibitor palbociclib reversibly arrest in the G

Zhang J, Li S, Shang Z, et al.
Targeting the overexpressed ROC1 induces G2 cell cycle arrest and apoptosis in esophageal cancer cells.
Oncotarget. 2017; 8(17):29125-29137 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Recent reports showed that regulator of Cullins-1 (ROC1) play an important role in tumor progression in a tumor-specific manner. However, the role and mechanism of ROC1 in esophageal cancer remains elusive. Here we demonstrated that ROC1 was overexpressed in esophageal squamous cell carcinomas, which was positive associated with poor prognosis of esophageal cancer patients. ROC1 knockdown significantly inhibited the growth of esophageal cancer cells in vitro and in vivo. Mechanistically, ROC1 silencing induced G2 cell cycle arrest and triggered apoptosis by accumulating the pro-apoptotic protein NOXA. Consistently, the downregulation of NOXA expression via siRNA substantially attenuated apoptosis induced by ROC1 silencing. These findings suggest that ROC1 is an appealing drug target for esophageal cancer.

Jandial DD, Krill LS, Chen L, et al.
Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin.
Molecules. 2017; 22(3) [PubMed] Article available free on PMC after 10/09/2019 Related Publications
HER2/neu positive breast tumors predict a high mortality and comprise 25%-30% of breast cancer. We have shown that Flavokawain A (FKA) preferentially reduces the viabilities of HER2-overexpressing breast cancer cell lines (i.e., SKBR3 and MCF7/HER2) versus those with less HER2 expression (i.e., MCF7 and MDA-MB-468). FKA at cytotoxic concentrations to breast cancer cell lines also has a minimal effect on the growth of non-malignant breast epithelial MCF10A cells. FKA induces G2M arrest in cell cycle progression of HER2-overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and downregulation of expression of Myt1 and Wee1 leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl₂, Bcl

Zheng H, Shao F, Martin S, et al.
WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance.
Sci Rep. 2017; 7:43517 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance.

Duan Z, Gao Y, Shen J, et al.
miR-15b modulates multidrug resistance in human osteosarcoma in vitro and in vivo.
Mol Oncol. 2017; 11(2):151-166 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
The development of multidrug resistance (MDR) in cancer cells to chemotherapy drugs continues to be a major clinical problem. MicroRNAs (miRNA, miR) play an important role in regulating tumour cell growth and survival; however, the role of miRs in the development of drug resistance in osteosarcoma cells is largely uncharacterized. We sought to identify and characterize human miRs that act as key regulators of MDR in osteosarcoma. We utilized a miR microarray to screen for differentially expressed miRs in osteosarcoma MDR cell lines. We determined the mechanisms of the deregulation of expression of miR-15b in osteosarcoma MDR cell lines, and its association with clinically obtained tumour samples was examined in tissue microarray (TMA). The significance of miR-15b in reversing drug resistance was evaluated in a mouse xenograft model of MDR osteosarcoma. We identified miR-15b as being significantly (P < 0.01) downregulated in KHOS

Li P, Yang Y, Liu H, et al.
MiR-194 functions as a tumor suppressor in laryngeal squamous cell carcinoma by targeting Wee1.
J Hematol Oncol. 2017; 10(1):32 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
The emerging roles of microRNAs (miRs) have been deeply investigated in cancer. However, the role of miR-194 in human laryngeal squamous cell carcinoma (LSCC) is still unclear. Here, we have demonstrated that miR-194 is significantly downregulated in LSCC tissues and cells, and overexpression of miR-194 inhibits the proliferation, migration, invasion, and drug resistance in LSCC cells. Moreover, Wee1 is identified as a novel direct target of miR-194. Ectopic expression of Wee1 at least in part overcomes the suppressive impacts of miR-194 on the malignant phenotypes of LSCC. Overall, our study provides new sights into the role of miR-194/Wee1 axis in LSCC and suggests a novel miR-194/Wee1-based clinical application for LSCC patients.

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Cite this page: Cotterill SJ. WEE1, Cancer Genetics Web: http://www.cancer-genetics.org/WEE1.htm Accessed:

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