CRISPR/Cas9: a powerful tool for identification of new targets for cancer treatment

Liu, Bin; Saber, Aly; Haisma, Hidde J.

doi:10.1016/j.drudis.2019.02.011

Cited by 63 publications

(46 citation statements)

References 195 publications

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“…Important advancements in the discovery of carcinogenesis and molecular targets have been achieved in vitro with the powerful CRISPR/Cas9 gene editing system, a genetic tool able to identify and execute cleavage at specific DNA sites [85]. One example of CRISPR/Cas9 application in CCA is the recent work by Yoshino et al in which the role of ARID1A (AT-rich interactive domain-containing protein 1A) was investigated by means of gene editing.…”

Section: D Models: Cell Lines and Primary Cell Culturesmentioning

confidence: 99%

Evolution of the Experimental Models of Cholangiocarcinoma

Massa

Varamo

Vita

et al. 2020

Cancers

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Cholangiocarcinoma (CCA) is a rare, aggressive disease with poor overall survival. In advanced cases, surgery is often not possible or fails; in addition, there is a lack of effective and specific therapies. Multidisciplinary approaches and advanced technologies have improved the knowledge of CCA molecular pathogenesis, highlighting its extreme heterogeneity and high frequency of genetic and molecular aberrations. Effective preclinical models, therefore, should be based on a comparable level of complexity. In the past years, there has been a consistent increase in the number of available CCA models. The exploitation of even more complex CCA models is rising. Examples are the use of CRISPR/Cas9 or stabilized organoids for in vitro studies, as well as patient-derived xenografts or transgenic mouse models for in vivo applications. Here, we examine the available preclinical CCA models exploited to investigate: (i) carcinogenesis processes from initiation to progression; and (ii) tools for personalized therapy and innovative therapeutic approaches, including chemotherapy and immune/targeted therapies. For each model, we describe the potential applications, highlighting both its advantages and limits.

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Section: D Models: Cell Lines and Primary Cell Culturesmentioning

confidence: 99%

Evolution of the Experimental Models of Cholangiocarcinoma

Massa

Varamo

Vita

et al. 2020

Cancers

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“…Given the importance of EGFR overexpression for tumor survival, growth and drug resistance, future studies are needed to explore whether overexpressed EGFR knockout can be an option for more cancers [22]. However, for clinical use, optimization of the delivery methods for specifically targeting overexpressed EGFR in cancer cells needs more in depth investigations [23]; for instance, optimization of specific gene therapy delivery vehicles based on EGFR [24] We showed a higher level of MAPK/pERK in RC21 EGFR -/cells as compared to the EGFR wt/wt cells indicative of a bypass mechanism for activation of MAPK/pERK pathway upon loss of EGFR. We observed that the proliferation of RC21 EGFR -/can be inhibited by sunitinib.…”

Section: Plos Onementioning

confidence: 99%

“…These two key pathways are common therapeutic targets for cancer therapy. In this study, we investigated EGFR knockout as a therapeutic option in RCC using CRISPR/Cas9 [8][9][10]. We also evaluated the inhibitory effects of multiple inhibitors as well as alterations in PI3K/AKT and RAS/RAF/MEK/ERK downstream pathways in the EGFR wt/wt and EGFR -/renal cancer cells.…”

Section: Introductionmentioning

confidence: 99%

CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

et al. 2020

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Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR-/cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/ M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/ Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma.

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“…The A549, H1299, H1650 EGFR -/cell lines were generated by using CRISPR/Cas9 gene editing technology ( Supplementary Fig. 1A) 16,24 .…”

Section: Establishment Of Egfr -/And Egfr-tki Resistant Cell Linesmentioning

confidence: 99%

Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma

Liu

Deng

Chen

et al. 2019

Preprint

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Several different mechanisms are implicated in the resistance of lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and only few have been functionally investigated. Here, using genetically knocked out EGFR and TKI-resistant lung cancer cells, we show that loss of wild-type EGFR attenuates cell proliferation, migration and 3D-spherid formation, whereas loss of mutant EGFR or resistance to TKIs reinforces those processes. Consistently, disruption of wild-type EGFR leads to suppression of HER2/HER3, while mutant EGFR ablation or resistance to TKIs increases HER2/HER3 expression, compensating for EGFR loss. Furthermore, HER2/HER3 nuclear translocation mediates overexpression of cyclin D1, leading to tumor cell survival and drug resistance. Cyclin D1/CDK4/6 inhibition resensitizes erlotinib-resistant (ER) cells to erlotinib. Analysis of cyclin D1 expression in patients with nonsmall cell lung carcinoma (NSCLC) showed that its expression is negatively associated with overall survival and disease-free survival. Our results provide biological and mechanistic insights into targeting EGFR and TKI resistance.

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CRISPR/Cas9: a powerful tool for identification of new targets for cancer treatment

Cited by 63 publications

References 195 publications

Evolution of the Experimental Models of Cholangiocarcinoma

Evolution of the Experimental Models of Cholangiocarcinoma

CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma

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