scholarly journals Prioritisation of oncology therapeutic targets using CRISPR-Cas9 screening

2018 ◽  
Author(s):  
Fiona M Behan ◽  
Francesco Iorio ◽  
Emanuel Gonçalves ◽  
Gabriele Picco ◽  
Charlotte M Beaver ◽  
...  
Keyword(s):  
Drug Development ◽  
Werner Syndrome ◽  
Human Cancer ◽  
Target Identification ◽  
Recq Helicase ◽  
Human Cancer Cell Lines ◽  
Fitness Effects ◽  
Candidate Target ◽  
Cancer Types ◽  
Genome Scale

SummaryFunctional genomics approaches can overcome current limitations that hamper oncology drug development such as lack of robust target identification and clinical efficacy. Here we performed genome-scale CRISPR-Cas9 screens in 204 human cancer cell lines from 12 cancer-types and developed a data-driven framework to prioritise cancer therapeutic candidates. We integrated gene cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritise new oncology targets in defined tissues and genotypes. Furthermore, we took one of our most promising dependencies, Werner syndrome RecQ helicase, and verified it as a candidate target for tumours with microsatellite instability. Our analysis provides a comprehensive resource of cancer dependencies, a framework to prioritise oncology targets, and nominates specific new candidates. The principles described in this study can transform the initial stages of the drug development process contributing to a new, diverse and more effective portfolio of oncology targets.

scholarly journals Transporter associated with antigen processing 1 (TAP1) expression and prognostic analysis in breast, lung, liver, and ovarian cancer

2021 ◽  
Author(s):  
Anika Tabassum ◽  
Md. Nazmus Samdani ◽  
Tarak Chandra Dhali ◽  
Rahat Alam ◽  
Foysal Ahammad ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Cancer Progression ◽  
Antigen Processing ◽  
Human Cancer ◽  
Analytical Data ◽  
Significant Negative Correlation ◽  
Cancer Tissue ◽  
Human Cancer Cell Lines ◽  
Prognostic Analysis ◽  
Cancer Types

Abstract Transporter associated with antigen processing 1 (TAP1) is a transporter protein that represent tumor antigen in the MHC I or HLA complex. Any defect in the TAP1 gene resulting in inadequate tumor tracking. TAP1 influences multidrug resistance (MDR) in human cancer cell lines and hinders the treatment during chemotherapeutic. The association of TAP1 in cancer progression remains mostly unknown and further study of the gene in relation with cancer need to conduct. Thus, the study has designed to analyze the association between the TAP1 with cancer by computationally. The expression pattern of the gene has determined by using ONCOMINE, GENT2, and GEPIA2 online platforms. The protein level of TAP1 was examined by the help of Human Protein Atlas. Samples with different clinical outcomes were investigated to evaluate the expression and promoter methylation in cancer vs. normal tissues by using UALCAN server. The copy number alteration, mutation frequency, and expression level of the gene in different cancer were analyzed by using cBioPortal server. The PrognoScan and KM plotter platforms were used to perform the survival analysis and represented graphically. Additionally, pathway and gene ontology (GO) features correlated to the TAP1 gene were analyzed and presented by bar charts. After arranging the data in a single panel like correlating expression to prognosis, mutational and alterations characteristic, and pathways analysis, we observed some interesting insights that emphasized the importance of the gene in cancer progression. The study found the relationship between the TAP1 expression pattern and prognosis in different cancer tissues and shows how TAP1 affects the clinical characteristics. The analytical data presented in the study is vital to learn about the effect of TAP1 in tumor tissue, where previously studies showing contradicting expression of TAP1 in cancer tissue. The analyzed data can also be utilized further to evade the threats against chemotherapy. Overall, the study provided a new aspect to consider the role of TAP1 gene in cancer progression and survival status. Key messages • This study demonstrated, for the first time, a correlation between the TAP1 gene and tumor progression. • An upregulation of TAP1 mRNA was demonstrated in various cancer types. • This study reported a significant negative correlation for TAP1 gene expression and the survival rate in different cancer types.

scholarly journals Regulatory mechanisms of phosphatase of regenerating liver (PRL)-3

2016 ◽  
Vol 44 (5) ◽  
pp. 1305-1312 ◽  
Author(s):  
Teresa Rubio ◽  
Maja Köhn
Keyword(s):  
Drug Development ◽  
Posttranslational Modifications ◽  
Human Cancer ◽  
Regulatory Mechanisms ◽  
Therapeutic Drug ◽  
Regenerating Liver ◽  
Cancer Types ◽  
Tumor Metastases ◽  
Phosphatase Of Regenerating Liver ◽  
Incomplete Picture

The phosphatase of regenerating liver (PRL)-3 is overexpressed in many human cancer types and tumor metastases when compared with healthy tissues. Different pathways and mechanisms have been suggested to modulate PRL-3 expression levels and activity, giving some valuable insights but still leaving an incomplete picture. Investigating these mechanisms could provide new targets for therapeutic drug development. Here, we present an updated overview and summarize recent findings concerning the different PRL-3 expression regulatory mechanisms and posttranslational modifications suggested to modulate the activity, localization, or stability of this phosphatase.

scholarly journals Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Pouyan Ghaffari ◽  
Adil Mardinoglu ◽  
Anna Asplund ◽  
Saeed Shoaie ◽  
Caroline Kampf ◽  
...  
Keyword(s):  
Growth Factors ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Metabolic Modeling ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Genome Scale

scholarly journals Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma

2020 ◽  
Vol 12 (562) ◽  
pp. eaba4434
Author(s):  
Karin Hansson ◽  
Katarzyna Radke ◽  
Kristina Aaltonen ◽  
Jani Saarela ◽  
Adriana Mañas ◽  
...  
Keyword(s):  
High Risk ◽  
Human Cancer ◽  
Neuroblastoma Cell ◽  
Human Tumor ◽  
Loss Of Function ◽  
Human Cancer Cell Lines ◽  
Dismal Prognosis ◽  
Tumor Types ◽  
Genome Scale

Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.

scholarly journals A Profile of the In Vitro Anti-Tumor Activity and In Silico ADME Predictions of Novel Benzothiazole Amide-Functionalized Imidazolium Ionic Liquids

2019 ◽  
Vol 20 (12) ◽  
pp. 2865 ◽  
Author(s):  
Fawzia Al-blewi ◽  
Nadjet Rezki ◽  
Arshi Naqvi ◽  
Husna Qutb Uddin ◽  
Salsabeel Al-Sodies ◽  
...  
Keyword(s):  
Ionic Liquids ◽  
In Silico ◽  
Human Cancer ◽  
Biological Data ◽  
Anticancer Activities ◽  
Imidazolium Ionic Liquids ◽  
Human Cancer Cell Lines ◽  
Colon Cancers ◽  
Cancer Types

A focused array of green imidazolium ionic liquids (ILs) encompassing benzothiazole ring and amide linkage were designed and synthesized using quaternization and metathesis protocols. The synthesized ILs have been fully characterized by usual spectroscopic methods and screened for their anticancer activities against human cancer cell lines originating from breast and colon cancers. Collectively, our biological data demonstrate that the newly synthesized series has variable anticancer activities in the examined cancer types. The synthesized ILs 8, 10 and 21–29 comprising the methyl and methyl sulfonyl benzothiazole ring emerged as the most potent compounds with promising antiproliferative activities relative to their benzothiazole ring counterparts. Furthermore, the mechanism underlying the observed anticancer activity was investigated. The most active compound 22 appears to exert its anticancer effect through apoptosis dependent pathway in breast cancer cells. Interestingly, compound 22 has also shown good in silico absorption (81.75%) along with high gastro-intestinal absorption as per ADME predictions.

scholarly journals Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Brenton R Paolella ◽  
William J Gibson ◽  
Laura M Urbanski ◽  
John A Alberta ◽  
Travis I Zack ◽  
...  
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Copy Number Alterations ◽  
Wild Type ◽  
Partial Loss ◽  
Human Cancer Cell Lines ◽  
Human Cancer Cells ◽  
A Genome ◽  
Genome Scale ◽  
Somatic Copy Number Alterations

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency.

Synthesis and in vitro evaluation of naphthalimide–benzimidazole conjugates as potential antitumor agents

2019 ◽  
Vol 17 (21) ◽  
pp. 5349-5366 ◽  
Author(s):  
Iqubal Singh ◽  
Vijay Luxami ◽  
Kamaldeep Paul
Keyword(s):  
Biological Activity ◽  
Cell Lines ◽  
Antitumor Agents ◽  
Human Cancer ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Cancer Types ◽  
First Time ◽  
Potential Antitumor

A novel series of benzimidazole-naphthalimide conjugates was synthesized for the first time and screened for in vitro biological activity for 60 human cancer cell lines representing nine different cancer types.

scholarly journals Tankyrase inhibition sensitizes cells to CDK4 blockade

2019 ◽  
Author(s):  
Miguel Foronda ◽  
Yusuke Tarumoto ◽  
Emma M. Schatoff ◽  
Benjamin I. Leach ◽  
Bianca J Diaz ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Human Cancer ◽  
Human Cancer Cell Lines ◽  
Cycle Arrest ◽  
Crispr Screen ◽  
Positive Regulators ◽  
Cancer Types ◽  
G1 Cell Cycle Arrest ◽  
Canonical Wnt ◽  
Cdk4 Inhibition

AbstractTankyrase (TNKS) 1/2 are positive regulators of WNT signaling by controlling the activity of the β-catenin destruction complex. TNKS inhibitors provide an opportunity to suppress hyperactive WNT signaling in tumors, however, they have shown limited anti-proliferative activity as a monotherapy in human cancer cell lines. Here we perform a kinome-focused CRISPR screen to identify potential effective drug combinations with TNKS inhibition. We show that the loss of CDK4, but not CDK6, synergizes with TNKS1/2 blockade to drive G1 cell cycle arrest and senescence. Through precise modelling of cancer-associated mutations using cytidine base editors, we show that this therapeutic approach is absolutely dependent on suppression of canonical WNT signaling by TNKS inhibitors and is effective in cells from multiple epithelial cancer types. Together, our results suggest that combined WNT and CDK4 inhibition might provide a potential therapeutic strategy for difficult-to-treat epithelial tumors.

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