p53 mutations induced by the MDM2 inhibitor nutlin-3 in p53 wild-type neuroblastoma cells

• Published in: European journal of cancer (1990) Vol. 69; p. S72
• Main Authors: Michaelis, M, Wass, M, Cinatl, J
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science Ltd 01-12-2016
• Subjects: Adaptation; Biotechnology; Cancer; Cancer therapies; Clinical trials; Cytotoxicity; Hematology, Oncology and Palliative Medicine; Inhibitors; MDM2 protein; Mutation; Neuroblastoma; Neuroblasts; p53 Protein; Tumor cell lines
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32806-4

Background: We and others showed that adaptation of wild-type p53 cell lines from different cancer entities to the MDM2 inhibitor nutlin-3 results in p53 mutations in the majority of the resulting nutlin-3-resistant sublines. In contrast, adaptation of wild-type p53 cancer cell lines to RITA (inhibits the p53-MDM2 interaction by binding to p53) did not result in loss-of-p53 function. Using single p53 wild-type cell-derived clonal cell lines we demonstrated that nutlin-3 induces de novo p53 mutations. However, the origin of the nutlin-3-induced p53 mutations remains unclear. Material and Methods: In the meantime, we have established 94 nutlin-3-resistant cancer cell lines by continuous exposure to step-wise increasing nutlin-3 concentrations. The p53 mutational status of these cell lines was determined by sequencing. Results: 72 out of these 94 nutlin-3-adapted cell lines (77%) harboured various p53 mutations while only 2 out of 28 sub-lines of the same cell lines adapted to various cytotoxic drugs harboured p53-mutations. The panel of nutlin-3-resistant cell lines includes 67 cell lines that were established from seven single p53 wild-type cell-derived sub-clones of the neuroblastoma cell line UKF-NB-3. Individual sub-clones differed in their p53 mutation profiles in response to adaptation to nutlin-3. Conclusions: Our data suggest that cell-specific features that differ between clonal sub-lines of the same parental cell line influence the nature and frequency of nutlin-3-induced p53 mutations.