TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation
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Catherine J. Drummond1,*, Arman Esfandiari1,*, Junfeng Liu1, Xiaohong Lu1, Claire Hutton1, Jennifer Jackson1, Karim Bennaceur1, Qing Xu1, Aditya Rao Makimanejavali1, Fabio Del Bello2, Alessandro Piergentili2, David R. Newell1, Ian R. Hardcastle1, Roger J. Griffin1, John Lunec1
1Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom
2Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Camerino, Italy
*Joint first authors
John Lunec, email: email@example.com
Keywords: MDM2 inhibitor, Nutlin-3, MI-63, resistance, MDM2-amplification
Received: March 19, 2016 Accepted: May 29, 2016 Published: June 15, 2016
Non-genotoxic reactivation of the p53 pathway by MDM2-p53 binding antagonists is an attractive treatment strategy for wild-type TP53 cancers. To determine how resistance to MDM2/p53 binding antagonists might develop, SJSA-1 and NGP cells were exposed to growth inhibitory concentrations of chemically distinct MDM2 inhibitors, Nutlin-3 and MI-63, and clonal resistant cell lines generated. The p53 mediated responses of parental and resistant cell lines were compared. In contrast to the parental cell lines, p53 activation by Nutlin-3, MI-63 or ionizing radiation was not observed in either the SJSA-1 or the NGP derived cell lines. An identical TP53 mutation was subsequently identified in both of the SJSA-1 resistant lines, whilst one out of three identified mutations was common to both NGP derived lines. Mutation specific PCR revealed these mutations were present in parental SJSA-1 and NGP cell populations at a low frequency. Despite cross-resistance to a broad panel of MDM2/p53 binding antagonists, these MDM2-amplified and TP53 mutant cell lines remained sensitive to ionizing radiation (IR). These results indicate that MDM2/p53 binding antagonists will select for p53 mutations present in tumours at a low frequency at diagnosis, leading to resistance, but such tumours may nevertheless remain responsive to alternative therapies, including IR.
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