Inhibition of DNA-PKcs activity re-sensitizes uveal melanoma cells to radio- and chemotherapy.

Inhibition of DNA-PKcs activity re-sensitizes uveal melanoma cells to radio- and chemotherapy.

Publication date: Nov 28, 2019

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Despite of important progress in the local therapy, high radioresistance in primary tumor and chemoresistance in metastatic disease are the major obstacles for UM therapy. Therefore, strategies to overcome resistance to radiation or chemotherapy in UM are urgently needed. In this study, we found that phosphorylation of DNA-PKcs, which is the key factor of non-homologous end joining (NHEJ) pathway, was remarkably overexpressed in ionizing radiation (IR)- and Selumetinib resistant UM cells. Increased amount of NHEJ events were also observed in resistant UM cells. Inhibition of DNA-PKcs by NU7441 significantly impaired DNA repair and re-sensitized resistant UM cells to radiation and Selumetinib both in vitro and in vivo. The results demonstrate increased DNA double strand break repair as a mechanism of resistance to ionizing radiation and Selumetinib, and identify DNA-PKcs as a promising target for radio-and chemotherapy in UM patients.

Zhang, B., Wu, H., Hao, J., Wu, Y., and Yang, B. Inhibition of DNA-PKcs activity re-sensitizes uveal melanoma cells to radio- and chemotherapy. 24987. 2019 Biochem Biophys Res Commun.

Concepts Keywords
Chemoresistance Chemotherapy
Chemotherapy Radiation
DNA Radiation therapy
Homologous Uveal melanoma
Ionizing Radiation Oncology
Metastatic Non-homologous end joining
NHEJ DNA repair
NHEJ Pathway Radiobiology
Phosphorylation Antineoplastic drugs
PKcs Chemotherapy
Primary Tumor Melanoma
Radiation Clinical medicine
Tumor Medicine
Uveal Melanoma Branches of biology
Chemotherapy
Radiation
Primary tumor

Semantics

Type Source Name
pathway REACTOME DNA Repair
drug DRUGBANK Selumetinib
disease MESH tumor
disease MESH uveal melanoma

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