7a). The ultimate goal is to enable highly selective and potent small molecule drug discovery and to expand the mechanisms to treat diseases, with targets previously inaccessible to small molecules. MCF-7 cells were grown in MEM with 10% fetal bovine serum, 0.01mg/mL human recombinant insulin and 10mML-glutamine. 2017;12(5):43147. 7a but with post progression survival (n=43). 2c and d). However, the paclitaxel treatment significantly inhibited the tumor growth of control cells (73%), compared to the TAOK3-overexpressed group (17%) at week 7 (Fig. After semi-quantitation, phosphorylation of p53 showed the largest enhanced in overexpression condition (Figure S5B). Approximately 20100g of protein was loaded in an SDS-PAGE (TRIS-based), and blotting was performed on a nitrocellulose membrane (Amersham, Arlington Heights, IL, USA). The discovery and evaluation of TAOK3-associated pathway analysis. * indicates p<0.05. c Fluorescence photography of TUNEL stain in Hs578T-VC and Hs578T-TAOK3 cells after treating paclitaxel. 2018;14(8):76877. 2004;4(4):25365. The sources further told the outlet that the DOJ personnel investigating Cassava specialize in examining whether companies or individuals have misled or defrauded investors, government agencies or consumers. The sources did not detail the focus of the probe and if anyone specific was being looked into. We also determined the cleavage of caspase-3 and PARP in apoptotic Hs578T cells with TAOK3 overexpression compared to the control with 0.1, 1 and 10M paclitaxel treatment after 24h incubation. c The patients only with adjuvant endocrine therapy (n=1873). 2015;35(5):182130. Article Using the bioinformatics tool Kaplan-Meier Plotter (https://kmplot.com/analysis/) [26], which contains both publicly available array profiles and clinical data, we evaluated whether TAOK3 was associated with the prognoses for breast cancer patients. There were no significant differences in caspase-3/7 activation observed at 24h in control cells treated with paclitaxel or in untreated cells. Raman M, Earnest S, Zhang K, Zhao Y, Cobb MH. c The cytotoxicity assay of paclitaxel in MB157 with TAOK3 overexpressed and control. b The relative caspase-3 activity in TAOK3-modified MB157 and BT483 cells treated with paclitaxel. We further investigated possible correlation of TAOK3 with other chemotherapy drugs. We found the TAOK3 protein expression level was positive correlated to paclitaxel IC50 values in breast cancer cell lines (Fig. 2018;233(3):2489501. The negative control, which contains the pGIPZ vector backbone with a portion of scrambled shRNA (non-silencing gene), was included in each coated plate. J Biol Chem. Next, we treated cells with the anti-microtubule drugs eribulin and vinorelbine [24]. The biotech reported early Wednesday that the FDA has raised issues regarding deficiencies in the New Drug Application (NDA) for linzagolix for uterine fibroids. We aimed to discover novel candidate protein targets to combat chemoresistance in breast cancer. For the screening method, we used a solid phase transfection system to produce shRNA lentivirus in 96 well plate. Gyorffy B, Lanczky A, Eklund AC, et al. The above results provide more evidence that TAOK3 is associated with breast cancer prognosis specifically after taxane treatment. Several mechanisms of taxane resistance has previously been described: overexpression of multidrug resistance protein (MDR) genes, class III -tubulin, and epithelial-mesenchymal transition [6,7,8,9,10]. Akritopoulou-Zanze I, Hajduk PJ. Efficacy and safety of eribulin in taxane-refractory patients in the 'real world'. Visconti R, Grieco D. Fighting tubulin-targeting anticancer drug toxicity and resistance. growth rate ), p53 (1:500, #sc-126, Santa Cruz), caspase-3, (1:1000, #9662, Cell Signaling Tech. Nat Protoc. Stable breast cancer cell lines with targeted shRNA and cDNA were generated with 10g/mL puromycin and blasticidin, respectively (InvivoGen, Hong Kong). These results indicate that the interaction with TAOK3 and p53 may not be critical to the cell death induced by paclitaxel. van t Veer LJ, Dai H, van de Vijver MJ, et al. pGIPZ-shRNA glycerol stocks were purchased from Open Biosystems. Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. Please note that your Petitions are being denied solely on the grounds that your requests are not the appropriate subject of a citizen petition, Cavazzoni wrote in her response to the firm. Our findings warrant further investigation into taxane-exposed tumors and any correlation with the effects of subsequent treatment with eribulin or vinorebine. In the future, TAOK3 as a molecular target in cancer treatment should be evaluated. (A) The bot blot image of phosphoprotein array between Hs578t-VC and Hs578t-TAOK3. Comparative studies of a new subfamily of human Ste20-like kinases: homodimerization, subcellular localization, and selective activation of MKK3 and p38. 2c). 8c). 8b). h The cytotoxicity assay of vinorelbine in Hs578T with TAOK3 overexpressed. Google Scholar. 2010;102(2):31624. We also stained a phosphoprotein array to determine the changes of various phosphokinase (Figure S5A). The experimental mice were injected with the cells at two sides: one side was injected with control cells and the other side was injected with the TAKO3-overexpressed clone. The activity values were normalized to the fluorescence intensity of AlamarBlue (Invitrogen, USA). Koo CY, Giacomini C, Reyes-Corral M, et al. BridGene Biosciences's latest funding round is Series B. BridGene Biosciences raised a total of $50.5M. e Tumor weight distribution of the six indicative groups of Hcc1806. 2013;12(8):167687. 4a). We performed RNA microarray analysis to analyze 522 genes from Hs578T cells with TAOK3 overexpression and Hcc1806 cells with TAOK3 knockdown (Fig. Protein concentration was determined with the BCA kit (Thermo Scientific, Rockford, USA) using BSA as the standard. Young K, Minchom A, Larkin J. BRIM-1, 2 and 3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation. CAS united states, Hippo Pathway Targeted Drug Development Summit , How technology can transform drug development pipelines for better patient outcomes, SAS and Carolina team up to accelerate development of antiviral drugs, Japanese pharmaceutical company uses Israels CytoReason for AI drug development, 5 Ways Social Media Can Make Drug Development More Patient-Centered, Personalized Medicine Market to Witness Huge Growth by 2030 | 3G Biotech, Quest Diagnostics, Laboratory Corporation of America, This is Ardee, 5 Best Bad Credit Debt Consolidation Loans with Guaranteed Decisions in 2022, The public deserves feedback on the drugs that governments support. 2018;68(1):730. 1c). J Biol Chem. SKBR3 cells were grown in McCoys 5A medium (Gibco, USA) supplemented with 10mML-glutamine and 10% fetal bovine serum. TAOK3 expression altered cell death in taxane-treated cells. 2007;11(6):498512. north america In this review, we discuss the central roles of YAP in lung cancer and present YAP as a novel target for treating resistance to targeted therapies and immunotherapies in lung cancer. Anti-breast cancer activity of LFM-A13, a potent inhibitor of polo-like kinase (PLK). Total RNA was extracted with the RNeasy Mini kit (Qiagen, USA) and qualified with a Bioanalyzer (Agilent Technologies, USA). 2017;44(6):232236. Our data shown that NF-B signaling was the most upregulated. TAOK3 cDNA was cloned from an ORF clone and sub-cloned into pLenti6.3 Gateway vector using Gateway cloning systems according to the manufacturers protocol (Invitrogen, USA). 1a, Table S1). 2017;13(11):9718. Select "Patients / Caregivers / Public" or "Researchers / Professionals" to filter your results. The other group included MINK1, TSSK2, MARK1, MARK2, WNK3, VRK3, and TAOK3; however, this group has rarely been mentioned. 6d). BridGene is a biotechnology company focused on discovering and developing small molecules that drug traditionally undruggable targets, providing new paths to treat diseases. Harnessing the power of proteomics for identification of oncogenic, druggable signalling pathways in cancer. The fold change of TAOK family in microarray with TAOK3 modulation. Targeting the breast Cancer Kinome. For general cytotoxicity assays, 2000 cells were seeded into each well 24h before drug treatment. Breast Cancer Res. ), phospho-p65 (1:2000, #3033, Cell Signaling Tech. Knock down of a top ranking gene, TAOK3, overcome taxane resistance in breast cancer both in vitro and in vivo. Approximately 20,000 cells were seeded onto the 96-well plate, and paclitaxel was added to the cells at 24h before the caspase assay. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. BMC Cancer. Tassi E, Biesova Z, Di Fiore PP, Gutkind JS, Wong WT. b The top-ranking kinase and transcription factor list of upstream analysis. The report noted, Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 5c, S4). Tumor sizes were measured weekly and volume was calculated by 1/2 ab2 mm3. The FDA rejected the petition several months later in February earlier this year. Our TAOK3-modulated microarray analysis indicated that NF-B signaling played a major upstream regulation role. Okano J, Rustgi AK. The platform allows BridGene to screen small molecules against a target in live cells to discover possible drug candidates, mainly in undruggable targets, including for cancers. Associate Editor Downregulated TAOK3 expression in breast cancer cells enhanced the response to the drugs in non-silenced cells (Fig. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): T.C Lai, H.L Hsieh, P.M.H Chang, M. Hsiao. drug development Over 80 key stakeholders from BridgeBio, Cancer Research UK, AstraZeneca, Orion Pharma, Faze Medicines, Inventiva, Zentalis Pharmaceuticals, Basilea Pharmaceuticals and many more have already confirmed their place as the industry continues to unlock critical pieces of the puzzle in understanding and exploiting this signaling pathway. Cell Physiol Biochem. b Tumor weight distribution among the four indicative groups. World J Urol. Yes-associated protein (YAP), an effector of the Hippo pathway, promotes the resistance of these targeted drugs and modulates tumor immunity in lung cancer. 6e). (A) The mitotic percentage changes of NF-B shRNAs and control in Hs578T overexpressed and control cells. However, some resistant cells can withstand mitotic catastrophe and survive. Google Scholar. * indicates p-values <0.05. c The distribution of sub-G1 percentage in TAOK3-modified MB157 cells treated with paclitaxel for 24h. The TAOK3 expression panel was detected by western blotting. Black circles indicate the candidates with >25% inhibition and p-value <0.05. b The second round of the cell toxicity assay of paclitaxel with candidate shRNA treatment. News Reporter Use of these cookies, which may be stored on your device, permits us to improve and customize your experience. Keep reading Endpoints with a free subscription Please, check the official event website for possible changes, before making any traveling arrangements, We use cookies to ensure you get the best experience on our website, ESMO Targeted Anticancer Therapies (TAT) Congress 2023, 4th International Conference on Nanomedicine and Drug delivery, International Summit on Hematology and Blood disorders, Comparison of immature life stages duration of Liriomyza trifolii (Dip. PubMedGoogle Scholar. Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas. Increased expression of MyD88 and association with paclitaxel resistance in breast cancer. Cinnamaldehyde derivative (CB-PIC) sensitizes chemo-resistant cancer cells to drug-induced apoptosis via suppression of MDR1 and its upstream STAT3 and AKT signalling. Google Scholar. NCCN guidelines insights breast Cancer, version 1.2016. Preparation for shRNA screening platform. 7c). ALK Positive, Inc. All Rights Reserved, New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development. d Expression of TAOK3, cleaved caspase-3, and PARP in Hs578T cells treated by paclitaxel for 24h. To access the effect of paclitaxel treatment on different TAOK3 expression levels in vivo, we determined the paclitaxel response effects in Hcc1806 and Hs578T using an in vivo subcutaneous xenograft tumor model. Innovative advancements in lung cancer treatment have developed over the past decade with the advent of targeted and immune therapies. To overcome the TAOK3 effects on paclitaxel resistance, we tested a specific inhibitor of the TAOK3 family, CP43 [25], and used NF-B shRNA on a TAOK3 overexpression clone. We selected the top 50 candidate genes whose knockdown induced paclitaxel sensitivities (listed in Table S2). 3f and h). However, the effect of CP43 on TAOK3 is unknown. The RNA expression levels of PTGS2, PLA2G4A, and PDE4B were determined with real-time PCR (Fig. In TAOK3 overexpression cells, cells exhibited higher drug resistance than the control group (Fig. Such results may indicate that inhibition of TAOK3-NF-B signaling is a potential treatment on reducing paclitaxel-resistance in breast cancer cells. Conception and design: M Hsiao, T.C Lai, H.L Hsieh. McCubrey JA, Steelman LS, Abrams SL, et al. All samples were analyzed using Affymetrix GeneChip Human Genome U133 plus 2.0 arrays according to the manufacturers instructions. In the Hcc1806-shTAOK3 groups, the data showed dose-dependent enhanced paclitaxel sensitivity (Fig. The expression of TAOK3 was positive correlative to the IC50 of paclitaxel in breast cancer cell lines (Fig. Murray S, Briasoulis E, Linardou H, Bafaloukos D, Papadimitriou C. Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies. market report Although there are no known specific inhibitors of TAOK3, there are several commercial NF-B inhibitors, and the inhibition of NF-B signaling could provide a putative resolution for TAOK3-associated anti-microtubule drug resistance. Future Oncol. 8a) rather than post progression survival (Fig. However, the mechanism of TAOK3-NF-B-PTGS2 pathway remains unclear. Cross-sections of alternative TAOK3 expression xenograft tumor without paclitaxel treatment with TAOK3 IHC staining. Companies researching, developing, or offering products & services that aid in the screening, prevention, diagnosis, management, and treatment of cancer. A comparison of the tumor weight between the 4 groups revealed significant inhibition after paclitaxel treatment in the control group (Fig. Katayama MLH, Vieira R, Andrade VP, et al. (B) The cytotoxicity of paclitaxel of NF-B shRNAs and control in Hs578T control cells. TAOK3 shRNA exhibited the most significant reduction in IC50 values in response to paclitaxel treatment. Stengel C, Newman SP, Leese MP, Potter BV, Reed MJ, Purohit A. Read More Acquisition of epithelial-mesenchymal transition is associated with Skp2 expression in paclitaxel-resistant breast cancer cells. b The percentage of mitotic cells after CP43 treatment for 24h in Hcc1806-shLuc, Hcc1806-shTAOK31 and Hcc1806-shTAOK32. The CB Insights tech market intelligence platform analyzes millions of data points on vendors, products, partnerships, and patents to help your team find their next technology solution. You can read more about your. One group included ABL2, YES1, BMX, and LCK, which have been associated with paclitaxel resistance [30,31,32,33]. 1998;273(44):2862532. As small molecule companies continue to get serious cash from investors as well as backing from major pharma companies such as Eli Lilly , California-based BridGene Biosciences is looking to stay ahead of the pack. The 3 most popular patent topics include: Monoclonal antibodies, Experimental cancer drugs, Monoclonal antibodies for tumors, Transcription factors, Oncology, Paul Schloesser This initial analysis suggests a pattern of clear errors and anomalies that are consistent with data manipulation and misrepresentation. 2b). Fgfr inhibitors for the treatment of cancer, DOJ opens criminal probe into Cassava over allegations of Alzheimer's drug data manipulation report, Versant and AbCellera go deeper on antibodies, pushing forward a trio of stealth companies, Teva to pay $4.3B to settle opioid epidemic litigation with states, A year after netting Takeda partnership, small molecule startup arms itself with some new cash, ObsEva implodes on warning that the FDA has set up a roadblock for its flagship drug. In our study, the overexpression of TAOK3 increased phosphorylation of NF-B. CBI websites generally use certain cookies to enable better interactions with our sites and services. et al. 2017;163(3):46174. Cell Physiol Biochem. Huang S, Wang D, Zhang S, et al. The content on the ALK Positive website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. In Hs578T cells, we found that CP43 increased the percentage of mitotic cells (histone H3-pS10-positive) in all clones; however, in TAOK3-overexpressed cells, the percentage increase was dose-dependent (Fig. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 2d). 6b). KaplanMeier plots of TAOK3 in different sub-cohorts of clinical breast cancer patients. 3c and d). Normally, cells that slip out of mitosis stop dividing, become senescent or die [53]. 2022 BioMed Central Ltd unless otherwise stated. 5d). The synergistic effect with paclitaxel was shown in TAOK3-overexpressed cells but not in controls. 2006;46:24979. One Burlington Mall Road Characterization of hippo pathway components by gene inactivation. 2014;110(8):195867. market players Oncogene. Bob Duggan is getting help in the chief executive spot. The suit is based on whether the drug would infringe on one of the patents that protect Jazz Pharmaceuticals treatment for narcolepsy Xywav which has been a primary treatment since 2002 and is distributed under a Risk Evaluation and Mitigation Strategy, or REMS. CAS our sites and services. Visualization of the western blots was performed using the ECL Pro set (PerkinElmer) and X-ray radiography. The discovery and characterisation of signalling pathways has been essential for understanding organism development, as well as human diseases. N Engl J Med. 2009;15(4):141727. In this study, we screened paclitaxel response-associated kinases and provided evidence that TAOK3 overexpression reduced the sensitivity to anti-microtubule drug in breast cancer cells and was correlated with poor outcomes in patients. PubMed 2015;13(12):147585. Study supervision: M. Hsiao. Hanson Wade's goal is to accelerate progress within organisations and across industries. TAOK3 shRNA initiated the most significant decline of paclitaxel IC50 values. Swanton C, Szallasi Z, Brenton JD, Downward J. Functional genomic analysis of drug sensitivity pathways to guide adjuvant strategies in breast cancer. Months after reports of allegations regarding Cassava Sciences lead drug candidate for Alzheimers emerged, the DOJ may now be raising its head to investigate the company. Google Scholar. In contrast, the sub-G1 percentage in the cell population with TAOK3 overexpressed did not dramatically increased after treatment with paclitaxel (Fig. Hutchison M, Berman KS, Cobb MH. statement and Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, 116, Taiwan, Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, 116, Taiwan, Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan, Tsung-Ching Lai,Chih-Yeu Fang,Yi-Hua Jan,Hsiao-Ling Hsieh&Michael Hsiao, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, 81362, Taiwan, Department of Oncology, Taipei Veterans General Hospital, Taipei, 11217, Taiwan, Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, 11217, Taiwan, Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, 11217, Taiwan, Faculty of Medicine, National Yang Ming University, Taipei, 112, Taiwan, Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan, The Ph.D.Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, You can also search for this author in Supplement Figure 6. Chen X, Sun X, Guan J, et al. All animal experiment protocol (1403-665) was approved by the Academia Sinica Institutional Animal Care and Unitization Committee. : Agromyzidae) in field and laboratory conditions, Validation of Palliative Prognostic Index for Terminal Cancer Patients in Hospice Consultation Setting in Taiwan, A Population based Colorectal Cancer Screening Program, GI and Oncologic Surgery - Unusal Presentations of Meckel`s Diverticulum, Hippo Pathway Targeted Drug Development Summit, How to streamline successful translation of candidates through the clinic & to the patient which is safe & effective, Case-studies that lead to a better understanding of the Hippo pathway, Modalities to drug the Hippo pathway, from small molecules inhibition and other ovel approaches, Augment ideal patient selection & how to utilize biomarkers to guide drug development, The value of leveraging the Hippo pathway for the crosstalk in associated pathways such as RAS, EGFR & PI3K, Selectivity & toxicity of TEAD, YAP & other high-value target inhibitors as a promising therapeutic. In cell cycle analysis, this effect of CP43 is similar to the effect of paclitaxel. A lentiviral shRNA-based high-throughput screening platform was designed and developed to screen the global kinome to find new therapeutic targets in paclitaxel-resistant breast cancer cells. YAP is involved in autophagy in lung cancer and plays a prominent role in forming the tubular structure in lung organoids and alveolar differentiation. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The overexpression of TAOK3 conferred the sensitive breast cancer cells with an increased resistance to paclitaxel (Fig. Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer. The top 50 candidate genes included many genes related to paclitaxel resistance, such as AKT1, SRC, etc., but to date, many have not been mentioned in the literature [27, 28]. In addition, we overexpressed TAOK3 in the low endogenous TAOK3 cells, Hs578T and MB157. Associate Editor We also evaluated the stability of the transfected, coating plates at different temperatures and time points. asia pacific Eribulin (Halaven, NerPharMa S.r.l., Italy) and vinorelbine (Navelbine, Pierre Fabre, France) were diluted in the growth medium. All authors read and approved the final manuscript. Clin Cancer Res. In addition, we also found that the necrosis area was decreased when tumor with TAOK3 overexpression but without paclitaxel treatment (Figure S7). The candidates that are showed in Fig. This difference was not observed in patients who accepted endocrine-only adjuvant treatments (Fig. pharmaceutical companies E:info@hansonwade.com, Marriott Burlington c. The stability of coating plates after storing in variant conditions. The cDNA was synthesized by reverse transcriptase (Stratagene, USA) at 42C. DNA extraction was performed in a 96-well plate using a semi-automated Biomek-FX liquid handler and a ChargeSwitch nucleic acid purification kit (Invitrogen, USA). a The cell toxicity assay of paclitaxel in variant breast cancer cell lines. Nuclear factor kappa-light-chain-enhancer of activated B cells, B-Raf murine sarcoma viral oncogene homolog B, The half maximal inhibitory concentration, Terminal deoxynucleotidyl transferase dUTP nick end labeling, Conserved helix-loop-helix ubiquitous kinase, cAMP-specific 3,5-cyclic phosphodiesterase 4B. d Diagram of shRNA screening procedure of breast cancer cells, Identification of TAOK3 with kinome shRNA screening in breast cancer cell lines. TAOK3 inhibitor, CP43, and shRNA of NF-B both reduced the paclitaxel resistance in TAOK3 overexpressed cells. Mitotic slippage is one of the primary mechanisms of action to paclitaxel [52]. Notably, the TAOK3-related growth inhibition or enhancement was paclitaxel-dependent, as no significant difference in cell growth were observed in cells with either TAOK3 shRNA or cDNA when compared to the control cells (Figure S3). The Hippo Pathway Targeted Drug Development Summit covers topics such as: The Hippo Pathway Targeted Drug Development Summit brings together: The Hippo Pathway Targeted Drug Development Summit might be held in 2023. TAOK3 modulation had no effect on the expression of TAOK1 or TAOK2 (Table S3). There are three known TAO kinases: TAOK1~3, which are activated by stress; for example, TAOK2 was found to render cells resistant to irradiation by enhancing the capability of initiating DNA damage-induced G2/M arrest [38]. These phenotypes were validated with an analysis of endogenous protein expression (Fig. (B) Bar chart of top 10 increasing phosphorylated proteins. New avenues have been opened to evolve the landscape of targetable nodes and therapeutic interventions, from small molecule approaches to novel modalities targeting the TEAD transcription complex. J Natl Compr Cancer Netw. In another experiment, we used shRNA NF-B to block TAOK3-NF-B signaling in TAOK3-overexpressed cells. 2a). The Hippo pathway is the last major signalling pathway to be discovered and is a key regulator of multiple biological processes including organ size, cell fate and stem cells.
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