TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation.
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.
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Catherine J
CJ
Drummond
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Arman
A
Esfandiari
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Junfeng
J
Liu
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Xiaohong
X
Lu
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Claire
C
Hutton
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Jennifer
J
Jackson
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Karim
K
Bennaceur
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Qing
Q
Xu
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Aditya Rao
AR
Makimanejavali
Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
Fabio
F
Del Bello
Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
Alessandro
A
Piergentili
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
David R
DR
Newell
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Ian R
IR
Hardcastle
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Roger J
RJ
Griffin
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
John
J
Lunec
D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology* / Q000528:radiation effects*; D006801:Humans; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
MDM2 inhibitor; MDM2-amplification; MI-63; Nutlin-3; resistance