Search results for: WEE1
#33630040 2021/02/25 To Up
Current Treatment Strategies and Future Directions for Extrapulmonary Neuroendocrine Carcinomas: A Review.Patients with extrapulmonary neuroendocrine carcinomas (EPNECs) receive essentially the same treatment as those with small cell lung cancer (SCLC) despite differences in origin, clinical course, and survival. This SCLC-based approach is attributable to the rarity of EPNECs, which impedes the use of randomized clinical trials. However, neuroendocrine carcinomas are becoming more common because of the increasing use of systemic cancer therapy for adenocarcinomas. This treatment can transdifferentiate certain adenocarcinomas into neuroendocrine carcinomas. In addition, the treatment landscape for SCLC is slowly changing, potentially impacting the treatment paradigms for EPNECs.
Johannes Stelwagen, Elisabeth G E de Vries, Annemiek M E Walenkamp
2130 related Products with: Current Treatment Strategies and Future Directions for Extrapulmonary Neuroendocrine Carcinomas: A Review.100μg100 mg1 g1 g500 50 ug 96 wells (1 kit)0.1 mg100ul100ug10 mg200ul
#33627846 2021/02/24 To Up
Author Correction: A novel WEE1 pathway for replication stress responses.
Ting Pan, Qi Qin, Chubing Nong, Shan Gao, Lili Wang, Bingcheng Cai, Ming Zhang, Chong Wu, Hanchen Chen, Tong Li, Dan Xiong, Guoliang Li, Shui Wang, Shunping Yan
1901 related Products with: Author Correction: A novel WEE1 pathway for replication stress responses.1,000 tests2 Pieces/Box200 mg25 g2 Pieces/Box0.1 mg50 assays10 mg2 Pieces/Box 1 G
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#33583218 // To Up
Knockdown of lncRNA X inactive specific transcript (XIST) radiosensitizes non-small cell lung cancer (NSCLC) cells through regulation of miR-16-5p/WEE1 G2 checkpoint kinase (WEE1) axis.Long non-coding RNA (lncRNA) X inactive specific transcript (XIST) is reported to play an oncogenic role in non-small cell lung cancer (NSCLC). However, the role of XIST in regulating the radiosensitivity of NSCLC cells remains unclear. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expressions of XIST and miR-16-5p in NSCLC in tissues and cells, and Western blot was used to assess the expression of WEE1 G2 checkpoint kinase (WEE1). Cell counting kit-8 (CCK-8), colony formation and flow cytometry assays were used to determine cell viability and apoptosis after NSCLC cells were exposed to different doses of X-rays. The interaction between XIST and miR-16-5p was confirmed by StarBase database, qRT-PCR and dual-luciferase reporter gene assays. TargetScan database was used to predict WEE1 as a target of miR-16-5p, and their targeting relationship was further validated by Western blot, qRT-PCR and dual-luciferase reporter gene assays. XIST was highly expressed in both NSCLC tissue and cell lines, and knockdown of XIST repressed NSCLC cell viability and cell survival, and facilitated apoptosis under the irradiation. MiR-16-5p was a target of XIST, and rescue experiments demonstrated that miR-16-5p inhibitors could reverse the role of XIST knockdown on radiosensitivity in NSCLC cells. WEE1 was validated as a target gene of miR-16-5p, and WEE1 could be negatively regulated by XIST. XIST promotes the radioresistance of NSCLC cells by regulating the expressions of miR-16-5p and WEE1, which can be a novel target for NSCLC therapy.
Ran Du, Feng Jiang, Yanhua Yin, Jinfen Xu, Xia Li, Likuan Hu, Xiuyu Wang
1967 related Products with: Knockdown of lncRNA X inactive specific transcript (XIST) radiosensitizes non-small cell lung cancer (NSCLC) cells through regulation of miR-16-5p/WEE1 G2 checkpoint kinase (WEE1) axis.
#33574575 2021/02/11 To Up
A novel WEE1 pathway for replication stress responses.DNA replication stress poses a severe threat to genome stability and is a hallmark of cancer as well as a target for cancer therapy. It is well known that the evolutionarily conserved protein kinase WEE1 regulates replication stress responses by directly phosphorylating and inhibiting the major cell cycle driver CDKs in many organisms. Here, we report a novel WEE1 pathway. We found that Arabidopsis WEE1 directly interacts with and phosphorylates the E3 ubiquitin ligase FBL17 that promotes the degradation of CDK inhibitors. The phosphorylated FBL17 is further polyubiquitinated and degraded, thereby leading to the accumulation of CDK inhibitors and the inhibition of CDKs. In strong support for this model, either loss of function of FBL17 or overexpression of CDK inhibitors suppresses the hypersensitivity of the wee1 mutant to replication stress. Intriguingly, human WEE1 also phosphorylates and destabilizes the FBL17 equivalent protein SKP2, indicating that this is a conserved mechanism. This study reveals that the WEE1-FBL17/SKP2-CKIs-CDKs axis is a molecular framework for replication stress responses, which may have clinical implications because the WEE1 inhibitor AZD1775 is currently in phase II clinical trial as an anticancer drug.
Ting Pan, Qi Qin, Chubing Nong, Shan Gao, Lili Wang, Bingcheng Cai, Ming Zhang, Chong Wu, Hanchen Chen, Tong Li, Dan Xiong, Guoliang Li, Shui Wang, Shunping Yan1,000 tests2 Pieces/Box200 mg25 g2 Pieces/Box0.1 mg50 assays10 mg2 Pieces/Box 1 G
#33564073 2021/02/09 To Up
MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma.Soft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, despite intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) have been shown to contribute to oncogenic translation via phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). However, little is known about the role of MNK1/2 and their downstream targets in STS. In this study, we show that depletion of either MNK1 or MNK2 suppresses cell viability, anchorage-independent growth, and tumorigenicity of STS cells. We also identify a compelling antiproliferative efficacy of a novel, selective MNK inhibitor ETC-168. Cellular responsiveness of STS cells to ETC-168 correlates positively with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1. Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage further clinical translation of MNK inhibitors for STS treatment.
Xin-Yu Ke, Ye Chen, Valarie Yu-Yan Tham, Ruby Yu-Tong Lin, Pushkar Dakle, Kassoum Nacro, Mark Edward Puhaindran, Peter Houghton, Angela Pang, Victor Kwanmin Lee, Ling-Wen Ding, Sigal Gery, Jeffrey Hill, Leilei Chen, Liang Xu, H Phillip Koeffler
2721 related Products with: MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma.50 ug 25 mg1000 tests100ug 5 G100.00 ul2.5 mg100ug
#33556453 2021/02/05 To Up
DNA damage response inhibitors: An avenue for TNBC treatment.The DNA damage response (DDR) is critical for the maintenance of genomic stability by sensing DNA damage, regulating cell cycle and initiating DNA repair. Drugs targeting DDR pathways have been increasingly exploited in treating various tumors. Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive tumor with constitutive activation of oncogenes, inducing replication stress and DNA damage, which require the DDR for survival. In addition, emerging studies have demonstrated that TNBC harbors aberrant genetic alterations in DDR pathways, such as a high frequency of p53 dysfunction and BRCA1/2 mutations. DDR alterations force TNBC to rely on the existing DDR pathways for survival, and make TNBC particularly sensitive to specific DDR inhibitors, such as high sensitivity of TNBC with BRCA1/2 mutations to PARP inhibitors. This review first and comprehensively covers the current status of the development of DDR inhibitors and discusses the mechanism of targeting the DDR in TNBC. Preclinical and clinical studies on inhibitors of the ATR-CHK1-WEE1 pathway and PARP inhibitors, the most studied inhibitors, and some other DDR inhibitors as monotherapy or combination therapy in TNBC are summarized. We also highlight the possible predictive biomarkers for these DDR inhibitors and their potential combination strategies with chemotherapy, radiotherapy or other targeted agents to optimize the efficacy of DDR inhibitors in TNBC treatment. In conclusion, this review discussed the recent considerations related to the use of DDR inhibitors for TNBC and provides a perspective to address future directions and potential therapeutic strategies for patients with TNBC.
Juan Jin, Zhonghua Tao, Jun Cao, Ting Li, Xichun Hu100ug1 ml 100ul100 ul0.2 mg100ug100ug100ug100 TESTS100ug Lyophilized0.1 ml100ug Lyophilized
#33552868 2020/12/16 To Up
Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance.Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model ( mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor is generated. mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL-XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoSRPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.
Fabienne Lamballe, Fahmida Ahmad, Yaron Vinik, Olivier Castellanet, Fabrice Daian, Anna-Katharina Müller, Ulrike A Köhler, Anne-Laure Bailly, Emmanuelle Josselin, Rémy Castellano, Christelle Cayrou, Emmanuelle Charafe-Jauffret, Gordon B Mills, Vincent Géli, Jean-Paul Borg, Sima Lev, Flavio Maina
1476 related Products with: Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance.100ul100ul100ul100ul100ul100ul 100ul
#33547427 2021/02/05 To Up
WEE1 inhibition after platinum resistance.
David Killock250ul48 assays 10mlx1096 assays 100ul1 Set100ul
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#33542435 2021/02/04 To Up
The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.
Stijn Moens, Peihua Zhao, Maria Francesca Baietti, Oliviero Marinelli, Delphi Van Haver, Francis Impens, Giuseppe Floris, Elisabetta Marangoni, Patrick Neven, Daniela Annibali, Anna A Sablina, Frédéric Amant
1691 related Products with: The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.1 mg100 ul1 mg1 mg100ug Lyophilized100ug Lyophilized50ul (1mg/ml)100ug Lyophilized100ug Lyophilized100ug Lyophilized100 ug100ug Lyophilized
#33529438 2021/02/02 To Up
Targeting DNA damage response pathways to activate the STING innate immune signaling pathway in human cancer cells.Activating stimulator of interferon genes to turn immunologically refractive cold tumor hot is an exciting therapeutic approach to increase the clinical responsiveness of some human cancers to immune checkpoint inhibitors. DNA damaging drugs and PARP inhibitors are two types of agents that have demonstrated this potential. Inhibitors of Chk1 or Wee1 induce DNA damage in cancer cells in predominantly the S-phase population. Increased cytoplasmic single-stranded and double-stranded DNA (dsDNA) from this DNA damage resulted in increased tank-binding kinase 1 (TBK1) phosphorylation in a range of cancer cell lines. However, despite robust increases in pTBK1, no downstream consequences of TBK1 phosphorylation were observed (namely no increase in pIRF3/7, interferon regulatory factor (IRF)-dependent gene expression or a type I IFN response). In combination with cytotoxic chemotherapy such as gemcitabine or camptothecin (CPT), Chk1 inhibition increased cytoplasmic dsDNA compared with the cytotoxic alone but attenuated the cytotoxic chemotherapy-induced increase in IRF1 protein and STAT1 phosphorylation through inhibition of nuclear RelB translocation. Despite increased cytoplasmic DNA and TBK1 activation, inhibition of Chk1, ataxia telangiectasia and Rad3-related protein, or Wee1 failed to activate a type I IFN response. We discuss the potential underlying mechanisms for this lack of IRF-dependent gene response and how this might influence the clinical strategies of combining Chk1 or Wee1 inhibitors with immune checkpoint inhibitors.
Joanne Wayne, Teresa Brooks, Alexandra Landras, Andrew J Massey
1177 related Products with: Targeting DNA damage response pathways to activate the STING innate immune signaling pathway in human cancer cells.2 Pieces/Box14 inhibitors2 Pieces/Box100 μg1.00 flask2 Pieces/Box7 inhibitors10 1.00 flask2 Pieces/Box1.5 x 10^6 cells
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