The novel chemical entity YTR107 inhibits recruitment of nucleophosmin to sites of DNA damage, suppressing repair of DNA double-strand breaks and enhancing radiosensitization.

Sekhar KR, Reddy YT, Reddy PN, Crooks PA, Venkateswaran A, McDonald WH, Geng L, Sasi S, Van Der Waal RP, Roti JL, Salleng KJ, Rachakonda G, Freeman ML
Clin Cancer Res. 2011 17 (20): 6490-9

PMID: 21878537 · PMCID: PMC3195947 · DOI:10.1158/1078-0432.CCR-11-1054

PURPOSE - Radiation therapy continues to be an important therapeutic strategy for providing definitive local/regional control of human cancer. However, oncogenes that harbor driver mutations and/or amplifications can compromise therapeutic efficacy. Thus, there is a need for novel approaches that enhance the DNA damage produced by ionizing radiation.

EXPERIMENTAL DESIGN - A forward chemical genetic approach coupled with cell-based phenotypic screening of several tumor cell lines was used to identify a novel chemical entity (NCE) that functioned as a radiation sensitizer. Proteomics, comet assays, confocal microscopy, and immunoblotting were used to identify the biological target.

RESULTS - The screening process identified a 5-((N-benzyl-1H-indol-3-yl)-methylene)pyrimidine-2,4,6(1H,3H,5H)trione as an NCE that radiosensitized cancer cells expressing amplified and/or mutated RAS, ErbB, PIK3CA, and/or BRAF oncogenes. Affinity-based solid-phase resin capture followed by liquid chromatography/tandem mass spectrometry identified the chaperone nucleophosmin (NPM) as the NCE target. SiRNA suppression of NPM abrogated radiosensitization by the NCE. Confocal microscopy showed that the NCE inhibited NPM shuttling to radiation-induced DNA damage repair foci, and the analysis of comet assays indicated a diminished rate of DNA double-strand break repair.

CONCLUSION - These data support the hypothesis that inhibition of DNA repair due to inhibition of NPM shuttling increases the efficacy of DNA-damaging therapeutic strategies.

©2011 AACR.

MeSH Terms (17)

Animals Barbiturates Cell Line, Tumor DNA Breaks, Double-Stranded DNA Damage DNA Repair Humans Indoles Mice Mice, Nude Molecular Chaperones Molecular Targeted Therapy Neoplasms Nuclear Proteins Radiation-Sensitizing Agents Radiation Tolerance Random Allocation

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