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Springer Nature [academic journals on nature.com], Cell Death and Disease, 12(2), p. e243-e243, 2011

DOI: 10.1038/cddis.2011.129

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Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells

Journal article published in 2011 by Martin Michaelis, Florian Rothweiler, Susanne Barth, J. Cinat, M. van Rikxoort, Marijke Van Rikxoort, M. van Rikxoort, Jaroslav Cinatl, Nadine Löschmann, Yvonne Voges, Rainer Breitling ORCID, Andreas von Deimling, F. Rödel, A. von Deimling, Kristoffer Weber and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3rNutlin 10 ??M, harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3rNutlin 10 ??M cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3rNutlin 10 ??M cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3rNutlin 10 ??M cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3rNutlin 10 ??M and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristineresistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells. ?? 2011 Macmillan Publishers Limited. All rights reserved.