Inhibition of Cyclin‐Dependent Kinase 5

Ardelt, Maximilian A.; Fröhlich, Thomas; Martini, Emanuele; Müller, Martin; Kanitz, Veronika; Atzberger, Carina; Cantonati, Petra; Messner, Matthias; Posselt, L.; Lehr, Thorsten; Wojtyniak, Jan-Georg; Ulrich, Melanie; Arnold, Georg J.; König, Lars; Parazzoli, Dario; Zahler, Stefan; Rothenfußer, Simon; Mayr, Doris; Gerbes, Alexander L.; Scita, Giorgio; Vollmar, Angelika M.; Pachmayr, Johanna

doi:10.1002/hep.30190

Cited by 45 publications

(46 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this model, the depletion of CDK5 by shRNA leads to the hyperphosphorylation of IRFBP2, increased IRF2 expression, and lower PD-L1 levels (68,69). In addition, CRISPR-mediated disruption of CDK5 in cancer cells results in suppression of tumor growth (69,70).…”

Section: (V) Cyclin-dependent Kinase 5 (Cdk5)supporting

confidence: 53%

“…Its inhibition confers antitumor immunity due to interference with interferon regulatory factor 2 (IRF2) and interferon regulatory factor-binding protein 2 (IRF2BP2) (66,67). Consistent with this model, the depletion of CDK5 by shRNA leads to the hyperphosphorylation of IRFBP2, increased IRF2 expression, and lower PD-L1 levels (68,69). In addition, CRISPR-mediated disruption of CDK5 in cancer cells results in suppression of tumor growth (69,70).…”

Section: (V) Cyclin-dependent Kinase 5 (Cdk5)mentioning

confidence: 81%

See 1 more Smart Citation

Using Gene Editing Approaches to Fine-Tune the Immune System

et al. 2020

View full text Add to dashboard Cite

Genome editing technologies not only provide unprecedented opportunities to study basic cellular system functionality but also improve the outcomes of several clinical applications. In this review, we analyze various gene editing techniques used to finetune immune systems from a basic research and clinical perspective. We discuss recent advances in the development of programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases. We also discuss the use of programmable nucleases and their derivative reagents such as base editing tools to engineer immune cells via gene disruption, insertion, and rewriting of T cells and other immune components, such natural killers (NKs) and hematopoietic stem and progenitor cells (HSPCs). In addition, with regard to chimeric antigen receptors (CARs), we describe how different gene editing tools enable healthy donor cells to be used in CAR T therapy instead of autologous cells without risking graft-versus-host disease or rejection, leading to reduced adoptive cell therapy costs and instant treatment availability for patients. We pay particular attention to the delivery of therapeutic transgenes, such as CARs, to endogenous loci which prevents collateral damage and increases therapeutic effectiveness. Finally, we review creative innovations, including immune system repurposing, that facilitate safe and efficient genome surgery within the framework of clinical cancer immunotherapies.

show abstract

Section: (V) Cyclin-dependent Kinase 5 (Cdk5)supporting

confidence: 53%

Section: (V) Cyclin-dependent Kinase 5 (Cdk5)mentioning

confidence: 81%

Using Gene Editing Approaches to Fine-Tune the Immune System

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Knockdown of METTL3 expression increased the number of autophagosomes and LC3 accumulation in HCC cells, indicating suppression of autophagy may reverse the m 6 A-dependent resistance to sorafenib, a molecular targeted drug that inhibits RAF/ MEK/ERK pathway and VEGFR/PDGFR pathway. Previous studies have reported that combination of anti-ANXA3 (Tong et al, 2018) or Cdk5 inhibition (Ardelt et al, 2019) with sorafenib acts as novel strategies to improve sorafenib response in HCC treatment. We applied combination of autophagy inhibitor with sorafenib for HCC treatment under hypoxia and obtained the significant sensitivity effects of the cells to sorafenib, suggesting another novel strategy for sorafenib-resistant HCC treatment.…”

Section: A Validation Of Biomarker Genes Related To Autophagy In Foxomentioning

confidence: 99%

RNA m ⁶ A methylation regulates sorafenib resistance in liver cancer through FOXO 3‐mediated autophagy

et al. 2020

View full text Add to dashboard Cite

N6‐methyladenosine (m6A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m6A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m6A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated m6A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m6A modification in the resistance of HCC to sorafenib therapy.

show abstract

“…Recently, several research groups have utilized CRISPR-based methods to understand the potential resistance mechanisms and increase the efficacy of sorafenib in hepatocellular carcinoma (HCC). Suppression of cyclin dependent kinase 5 (CDK5) combined with sorafenib resulted in a reduced cell proliferation and migration as well as suppression of HCC progression both in vitro and in vivo by interfering with intracellular trafficking mechanisms [43]. It has been shown that knockout of the fibroblast growth factor receptor (FGFR4) using CRISPR technology sensitizes HCC cancer cells to sorafenib [44].…”

Section: Liver Cancermentioning

confidence: 99%

CRISPR/Cas9 for overcoming drug resistance in solid tumors

et al. 2019

View full text Add to dashboard Cite

Objectives In this review, we focus on the application of clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated nuclease 9 (Cas9), as a powerful genome editing system, in the identification of resistance mechanisms and in overcoming drug resistance in the most frequent solid tumors. Data acquisition Data were collected by conducting systematic searching of scientific English literature using specific keywords such as Bcancer^, BCRISPR^and related combinations. Results The review findings revealed the importance of CRISPR/Cas9 system in understanding drug resistance mechanisms and identification of resistance-related genes such as PBRM1, SLFN11 and ATPE1 in different cancers. We also provided an overview of genes, including RSF1, CDK5, and SGOL1, whose disruption can synergize with the currently available drugs such as paclitaxel and sorafenib. Conclusion The data suggest CRISPR/Cas9 system as a useful tool in elucidating the molecular basis of drug resistance and improving clinical outcomes.

show abstract

Inhibition of Cyclin‐Dependent Kinase 5

Cited by 45 publications

References 50 publications

Using Gene Editing Approaches to Fine-Tune the Immune System

Using Gene Editing Approaches to Fine-Tune the Immune System

RNA m ⁶ A methylation regulates sorafenib resistance in liver cancer through FOXO 3‐mediated autophagy

CRISPR/Cas9 for overcoming drug resistance in solid tumors

Contact Info

Product

Resources

About

Inhibition of Cyclin‐Dependent Kinase 5

Cited by 45 publications

References 50 publications

Using Gene Editing Approaches to Fine-Tune the Immune System

Using Gene Editing Approaches to Fine-Tune the Immune System

RNA m 6 A methylation regulates sorafenib resistance in liver cancer through FOXO 3‐mediated autophagy

CRISPR/Cas9 for overcoming drug resistance in solid tumors

Contact Info

Product

Resources

About

RNA m ⁶ A methylation regulates sorafenib resistance in liver cancer through FOXO 3‐mediated autophagy