Identifying the determinants of response to MDM2 inhibition.
Previous reports have provided evidence that p53 mutation is a strong negative predictor of response to MDM2 inhibitors. However, this correlation is not absolute, as many p53Mutant cell lines have been reported to respond to MDM2 inhibition, while many p53WT cell lines have been shown not to respond. To better understand the nature of these exceptions, we screened a panel of 260 cell lines and noted similar discrepancies. However, upon extensive curation of this panel, these apparent exceptions could be eliminated, revealing a perfect correlation between p53 mutational status and MDM2 inhibitor responsiveness. It has been suggested that the MDM2-amplified subset of p53WT tumors might be particularly sensitive to MDM2 inhibition. To facilitate clinical testing of this hypothesis, we identified a rationally derived copy number cutoff for assignment of functionally relevant MDM2 amplification. Applying this cutoff resulted in a pan-cancer MDM2 amplification rate far lower than previously published.
Oncology Research, Amgen, Inc., Thousand Oaks, California, USA.
Anne Y
AY
Saiki
Oncology Research, Amgen, Inc., Thousand Oaks, California, USA.
Sean
S
Caenepeel
Genome Analysis Unit, Amgen, Inc., South San Francisco, California, USA.|Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA.
Elissa
E
Cosgrove
Biostatistics, Amgen, Inc., Seattle, Washington, USA.
Cheng
C
Su
Molecular Sciences, Amgen, Inc., Thousand Oaks, California, USA.
Michael
M
Boedigheimer
Oncology Research, Amgen, Inc., Thousand Oaks, California, USA.
Jonathan D
JD
Oliner
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005784:Gene Amplification; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
MDM2; TP53; amplification