A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097

Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53–HDM2 inhibitors, such as NVP-CGM097. DOI: http://dx.doi.org/10.7554/eLife.06498.001

[1]  E. Koonin,et al.  Regeneration of Peroxiredoxins by p53-Regulated Sestrins, Homologs of Bacterial AhpD , 2004, Science.

[2]  Xinbin Chen,et al.  The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis , 2002, Oncogene.

[3]  A. Levine,et al.  The p53 pathway: positive and negative feedback loops , 2005, Oncogene.

[4]  Thomas Tan,et al.  p53 Binds and Activates the Xeroderma Pigmentosum DDB2 Gene in Humans but Not Mice , 2002, Molecular and Cellular Biology.

[5]  J. Manfredi,et al.  Constitutive Expression of the Cyclin-dependent Kinase Inhibitor p21 Is Transcriptionally Regulated by the Tumor Suppressor Protein p53* , 1998, The Journal of Biological Chemistry.

[6]  P. Furet,et al.  The central valine concept provides an entry in a new class of non peptide inhibitors of the p53-MDM2 interaction. , 2012, Bioorganic & Medicinal Chemistry Letters.

[7]  Stephen N. Jones,et al.  Regulation of p53 stability by Mdm2 , 1997, Nature.

[8]  C. Prives,et al.  Unleashing the power of p53: lessons from mice and men. , 2006, Genes & development.

[9]  M. Hollstein,et al.  p53 and human cancer: the first ten thousand mutations. , 2000, Advances in cancer research.

[10]  M. Oren,et al.  mdm2 expression is induced by wild type p53 activity. , 1993, The EMBO journal.

[11]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[12]  D. Sonkin.  Expression signature based on TP53 target genes doesn't predict response to TP53-MDM2 inhibitor in wild type TP53 tumors , 2015, eLife.

[13]  M. Oren,et al.  The p53-Mdm2 module and the ubiquitin system. , 2003, Seminars in cancer biology.

[14]  J. Marine,et al.  Mdm2-mediated ubiquitylation: p53 and beyond , 2010, Cell Death and Differentiation.

[15]  A. Levine,et al.  The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation , 1992, Cell.

[16]  J. Espinosa,et al.  Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactor recruitment. , 2001, Molecular cell.

[17]  Alan R. Fersht,et al.  Awakening guardian angels: drugging the p53 pathway , 2009, Nature Reviews Cancer.

[18]  S A Forbes,et al.  The Catalogue of Somatic Mutations in Cancer (COSMIC) , 2008, Current protocols in human genetics.

[19]  I. Krantz,et al.  KILLER/DR5 is a DNA damage–inducible p53–regulated death receptor gene , 1997, Nature Genetics.

[20]  C. Prives,et al.  Blinded by the Light: The Growing Complexity of p53 , 2009, Cell.

[21]  A. Levine,et al.  MDM2 is a central node in the p53 pathway: 12 years and counting. , 2005, Current cancer drug targets.

[22]  H. He,et al.  Ribosomal protein S27L is a direct p53 target that regulates apoptosis , 2007, Oncogene.

[23]  David P. Lane,et al.  Translating p53 into the clinic , 2010, Nature Reviews Clinical Oncology.

[24]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[25]  Rafael A. Irizarry,et al.  A summarization approach for Affymetrix GeneChip data using a reference training set from a large, biologically diverse database , 2006, BMC Bioinformatics.

[26]  M. Salgaller.  American Association for Cancer Research , 2000, Expert opinion on investigational drugs.

[27]  D. Wiest,et al.  Control of hematopoietic stem cell emergence by antagonistic functions of ribosomal protein paralogs. , 2013, Developmental cell.

[28]  Chris Harbron,et al.  RefPlus: an R package extending the RMA Algorithm , 2007, Bioinform..

[29]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[30]  S. Shinton,et al.  Ablation of Ribosomal Protein L22 Selectively Impairs αβ T Cell Development by Activation of a p53-Dependent Checkpoint , 2007 .

[31]  A. Levine,et al.  The p53-mdm-2 autoregulatory feedback loop. , 1993, Genes & development.

[32]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[33]  J. Ford,et al.  p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  C. Prives,et al.  Unleashing the power of p 53 : lessons from mice and men , 2006 .

[35]  P. Furet,et al.  Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53. , 2000, Journal of medicinal chemistry.

[36]  Yi Sun,et al.  Ribosomal protein S27-like and S27 interplay with p53-MDM2 axis s a target, a substrate, and a regulator , 2010, Oncogene.

[37]  D. Lane,et al.  What the papers say: The p53‐mdm2 autoregulatory feedback loop: A paradigm for the regulation of growth control by p53? , 1993 .

[38]  R. Myers,et al.  Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data , 2005, Nucleic acids research.

[39]  D. Beach,et al.  Cyclin G is a transcriptional target of the p53 tumor suppressor protein. , 1994, The EMBO journal.

[40]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[41]  A. Levine,et al.  Functions of the MDM2 oncoprotein , 1999, Cellular and Molecular Life Sciences CMLS.

[42]  Rongling Wu,et al.  A joint model for nonparametric functional mapping of longitudinal trajectory and time-to-event , 2006, BMC Bioinformatics.

[43]  R. Dowell,et al.  Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms , 2014, eLife.

[44]  G. Wahl,et al.  The p53 orchestra: Mdm2 and Mdmx set the tone. , 2010, Trends in cell biology.

[45]  H. Gaylord,et al.  AMERICAN ASSOCIATION FOR CANCER RESEARCH. , 1913, California state journal of medicine.

[46]  Darlene R. Goldstein,et al.  Partition resampling and extrapolation averaging: approximation methods for quantifying gene expression in large numbers of short oligonucleotide arrays , 2006, Bioinform..

[47]  Delbert Dueck,et al.  Clustering by Passing Messages Between Data Points , 2007, Science.

[48]  John Calvin Reed,et al.  Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. , 1994, Oncogene.

[49]  Yi-Song Wang,et al.  Wig-1, a new p53-induced gene encoding a zinc finger protein , 1997, Oncogene.

[50]  R. Verdun,et al.  p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage. , 2003, Molecular cell.

[51]  Karen H. Vousden,et al.  p53 in health and disease , 2007, Nature Reviews Molecular Cell Biology.

[52]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[53]  A. Levine,et al.  Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain , 1996, Science.

[54]  F. Tashiro,et al.  p53 target gene AEN is a nuclear exonuclease required for p53-dependent apoptosis , 2008, Oncogene.

[55]  A. Levine,et al.  The first 30 years of p53: growing ever more complex , 2009, Nature Reviews Cancer.

[56]  S. Shinton,et al.  Ablation of ribosomal protein L22 selectively impairs alphabeta T cell development by activation of a p53-dependent checkpoint. , 2007, Immunity.

[57]  Yusuke Nakamura,et al.  A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage , 2000, Nature.