CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer

Lan B, Zeng S, Zhang S, Ren X, Xing Y, Kutschick I, Pfeffer S, Frey B, Britzen-Laurent N, Grützmann R, Cordes N, Pilarsky C (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Cancers MDPI

Book Volume: 14

Article Number: 326

Journal Issue: 2

DOI: 10.3390/cancers14020326

Abstract

Although radiation therapy has recently made great advances in cancer treatment, the majority of patients diagnosed with pancreatic cancer (PC) cannot achieve satisfactory outcomes due to intrinsic and acquired radioresistance. Identifying the molecular mechanisms that impair the efficacy of radiotherapy and targeting these pathways are essential to improve the radiation response of PC patients. Our goal is to identify sensitive targets for pancreatic cancer radiotherapy (RT) using the kinome-wide CRISPR-Cas9 loss-of-function screen and enhance the therapeutic effect through the development and application of targeted inhibitors combined with radiotherapy. We transduced pancreatic cancer cells with a protein kinase library; 2D and 3D library cells were irradiated daily with a single dose of up to 2 Gy for 4 weeks for a total of 40 Gy using an X-ray generator. Sufficient DNA was collected for next-generation deep sequencing to identify candidate genes. In this study, we identified several cell cycle checkpoint kinases and DNA damage related kinases in 2D-and 3D-cultivated cells, including DYRK1A, whose loss of function sensitizes cells to radiotherapy. Additionally, we demonstrated that the harmine-targeted suppression of DYRK1A used in conjunction with radiotherapy increases DNA double-strand breaks (DSBs) and impairs homologous repair (HR), resulting in more cancer cell death. Our results support the use of CRISPR-Cas9 screening to identify new therapeutic targets, develop radiosensitizers, and provide novel strategies for overcoming the tolerance of pancreatic cancer to radiotherapy.

Authors with CRIS profile

Bin Lan Professur für Chirurgische Forschung Siyuan Zeng Professur für Chirurgische Forschung Shuman Zhang Professur für Chirurgische Forschung Xiaofan Ren Professur für Chirurgische Forschung Yuming Xing Professur für Chirurgische Forschung Sina Pfeffer Medizinische Fakultät Benjamin Frey Department of Radiation Oncology Nathalie Britzen-Laurent Professur für Molekulare und Experimentelle Chirurgie Robert Grützmann Lehrstuhl für Allgemein- und Viszeralchirurgie Christian Pilarsky Professur für Chirurgische Forschung

Involved external institutions

Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE)

How to cite

APA:

Lan, B., Zeng, S., Zhang, S., Ren, X., Xing, Y., Kutschick, I.,... Pilarsky, C. (2022). CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer. Cancers, 14(2). https://dx.doi.org/10.3390/cancers14020326

MLA:

Lan, Bin, et al. "CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer." Cancers 14.2 (2022).

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