A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a mouse model of human cancer, NVP-CGM097 exhibits favorable pharmacokinetic characteristics and impacted pharmacodynamic markers in human tumors, leading to tumor regression at well-tolerated dose levels.
“In a mouse model of human cancer, NVP-CGM097 exhibits favorable pharmacokinetic characteristics and impacted pharmacodynamic markers in human tumors, leading to tumor regression at well-tolerated dose levels.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [390]
In human p53 wild-type tumor cells, NVP-CGM097 binds to human MDM2 protein with a Ki value of 1.3 nM, activating p53 in human cells and inducing p53-dependent cell cycle arrest and apoptosis.
“In human p53 wild-type tumor cells, NVP-CGM097 binds to human MDM2 protein with a Ki value of 1.3 nM, activating p53 in human cells and inducing p53-dependent cell cycle arrest and apoptosis.389,390”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [390]
Cells with wild-type MDM2 and wild-type TP53 have unpredictable sensitivity to MDM2 inhibitors in glioblastoma and other tumor cell types.
“However, cells with wild-type MDM2 and wild-type TP53 have unpredictable sensitivity to MDM2 inhibitors in GBM and other tumor cell types22.”
From Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate (2016) · cites this paper as [22]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Irizarry, R. A. (2003) · Biostatistics · doi:10.1093/biostatistics/4.2.249 · Cited by 10,603 · see citing works
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., et al. (2012) · Nature · doi:10.1038/nature11003 · Cited by 7,950 · see citing works
Self-citationClustering by Passing Messages Between Data Points
Frey, B. J., & Dueck, D. (2007) · Science · doi:10.1126/science.1136800 · Cited by 6,733 · see citing works
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · see citing works
Blinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163 · see citing works
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,275 · see citing works
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206 · see citing works
Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo.
Miyashita, T., Krajewski, S., Krajewska, M., Wang, H., Lin, H., Liebermann, D. A., Hoffman‐Liebermann, B., & Reed, J. C. (1994) · PubMed · Cited by 2,143 · see citing works
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967 · see citing works
The p53 pathway: positive and negative feedback loops
Harris, S. L., & Levine, A. J. (2005) · Oncogene · doi:10.1038/sj.onc.1208615 · Cited by 1,967 · see citing works
The p53-mdm-2 autoregulatory feedback loop.
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1126 · Cited by 1,801 · see citing works
Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data
Dai, M. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni179 · Cited by 1,797 · see citing works
mdm2 expression is induced by wild type p53 activity.
Barak, Y., Juven, T., Haffner, R., & Oren, M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05678.x · Cited by 1,290 · see citing works
KILLER/DR5 is a DNA damage–inducible p53–regulated death receptor gene
Wu, G. S., Burns, T. F., McDonald, E. R., Jiang, W., Meng, R., Krantz, I. D., Kao, G., Gan, D.-D., Zhou, J.-Y., Muschel, R. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1097-141 · Cited by 1,081 · see citing works
p53 and Human Cancer: The First Ten Thousand Mutations
Hainaut, P. L., & Hollstein, M. C. (1999) · Advances in cancer research · doi:10.1016/s0065-230x(08)60785-x · Cited by 980 · see citing works
A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage
Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., & Nakamura, Y. (2000) · Nature · doi:10.1038/35003506 · Cited by 904 · see citing works
The Catalogue of Somatic Mutations in Cancer (COSMIC)
Forbes, S. A., Bhamra, G., Bamford, S., Dawson, E., Kok, C. Y., Clements, J., Menzies, A. H., Teague, J. W., Futreal, P. A., & Stratton, M. R. (2008) · Current Protocols in Human Genetics · doi:10.1002/0471142905.hg1011s57 · Cited by 899 · see citing works
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881 · see citing works
The p53–Mdm2 module and the ubiquitin system
Michael, D., & Oren, M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00099-8 · Cited by 759 · see citing works
Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD
Budanov, A. V., Sablina, A. A., Feinstein, E., Koonin, E. V., & Chumakov, P. M. (2004) · Science · doi:10.1126/science.1095569 · Cited by 731 · see citing works
Functions of the MDM2 oncoprotein
Freedman, D. A., Wu, L., & Levine, A. J. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050273 · Cited by 573 · see citing works
American Association for Cancer Research
Salgaller, M. L. (2000) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.9.6.1413 · Cited by 474 · see citing works
Cyclin G is a transcriptional target of the p53 tumor suppressor protein.
Okamoto, K., & Beach, D. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06807.x · Cited by 455 · see citing works
The p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
Espinosa, J. M., & Emerson, B. M. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00283-0 · Cited by 440 · see citing works
Translating p53 into the clinic
Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.174 · Cited by 381 · see citing works
Mdm2-mediated ubiquitylation: p53 and beyond
Marine, J.-C., & Lozano, G. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.68 · Cited by 354 · see citing works
p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene
Adimoolam, S., & Ford, J. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202485699 · Cited by 321 · see citing works
MDM2 is a Central Node in the p53 Pathway: 12 Years and Counting
Bond, G. L., Hu, W., & Levine, A. J. (2005) · Current Cancer Drug Targets · doi:10.2174/1568009053332627 · Cited by 310 · see citing works
Espinosa, J. M., Verdun, R. E., & Emerson, B. M. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00359-9 · Cited by 256 · see citing works
Garcı́a-Echeverrı́a, C., Chêne, P., Blommers, M. J. J., & Furet, P. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm990966p · Cited by 246 · see citing works
Self-citationAllen, M. A., Andrysík, Z., Dengler, V. L., Mellert, H. S., Guarnieri, A. L., Freeman, J. A., Sullivan, K. D., Galbraith, M. D., Luo, X., Kraus, W. L., et al. (2014) · eLife · doi:10.7554/elife.02200 · Cited by 238 · see citing works
Liu, G., & Chen, X. (2002) · Oncogene · doi:10.1038/sj.onc.1205862 · Cited by 207 · see citing works
Picksley, S. M., & Lane, D. P. (1993) · BioEssays · doi:10.1002/bies.950151008 · Cited by 207 · see citing works
Anderson, S. J., Lauritsen, J. P. H., Hartman, M. G., Foushee, A. M. D., Lefebvre, J. M., Shinton, S. A., Gerhardt, B., Hardy, R. R., Oravecz, T., & Wiest, D. L. (2007) · Immunity · doi:10.1016/j.immuni.2007.04.012 · Cited by 173 · see citing works
p53 Binds and Activates the Xeroderma Pigmentosum <i>DDB2</i> Gene in Humans but Not Mice
Tan, T., & Chu, G. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.10.3247-3254.2002 · Cited by 167 · see citing works
Xiong, X., Zhao, Y., He, H., & Sun, Y. (2010) · Oncogene · doi:10.1038/onc.2010.569 · Cited by 141 · see citing works
p53 target gene AEN is a nuclear exonuclease required for p53-dependent apoptosis
Kawase, T., Ichikawa, H., Ohta, T., Nozaki, N., Tashiro, F., Ohki, R., & Taya, Y. (2008) · Oncogene · doi:10.1038/onc.2008.32 · Cited by 105 · see citing works
Ribosomal protein S27L is a direct p53 target that regulates apoptosis
He, H., & Sun, Y. (2006) · Oncogene · doi:10.1038/sj.onc.1210073 · Cited by 105 · see citing works
Control of Hematopoietic Stem Cell Emergence by Antagonistic Functions of Ribosomal Protein Paralogs
Zhang, Y., Duc, A. E., Rao, S., Sun, X., Bilbee, A. N., Rhodes, M. R., Li, Q., Kappes, D. J., Rhodes, J., & Wiest, D. L. (2013) · Developmental Cell · doi:10.1016/j.devcel.2013.01.018 · Cited by 101 · see citing works
Unleashing the power of p53: lessons from mice and men: Figure 1.Preprint
Poyurovsky, M. V., & Prives, C. L. (2006) · Genes & Development · doi:10.1101/gad.1397506 · Cited by 96 · see citing works
Katz, S., Irizarry, R. A., Lin, X., Tripputi, M., & Porter, M. W. (2006) · BMC Bioinformatics · doi:10.1186/1471-2105-7-464 · Cited by 85 · see citing works
Furet, P., Chêne, P., Pover, A. D., Stachyra, T., Lisztwan, J. H., Kallen, J. A., & Masuya, K. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.03.083 · Cited by 73 · see citing works
Self-citationWig-1, a new p53-induced gene encoding a zinc finger protein
Varmeh-Ziaie, S., Okan, İ., Wang, Y., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1201454 · Cited by 73 · see citing works
Tang, H.-Y. J., Zhao, K., Pizzolato, J. F., Fonarev, M., Langer, J., & Manfredi, J. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.44.29156 · Cited by 70 · see citing works
RefPlus: an R package extending the RMA Algorithm
Harbron, C. G., Chang, K., & South, M. C. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btm357 · Cited by 67 · see citing works
A joint model for nonparametric functional mapping of longitudinal trajectory and time-to-event
Lin, M. J., & Wu, R. (2006) · BMC Bioinformatics · doi:10.1186/1471-2105-7-138 · Cited by 29 · see citing works
Sonkin, D. (2015) · eLife · doi:10.7554/elife.10279 · Cited by 20 · see citing works
Mechanistic study of NVP-CGM097: A potent, selective and species specific inhibitor of p53-Mdm2
Valat, M. T. (2015) · Drug Designing Open Access · doi:10.4172/2169-0138.s1.008 · Cited by 8 · see citing works
Goldstein, D. R. (2006) · Bioinformatics · doi:10.1093/bioinformatics/btl402 · Cited by 6 · see citing works
Jeay, S., Berghausen, J., Buschmann, N., Chêne, P., Cozens, R. M., Erdmann, D., Ferretti, S., Furet, P., Gabriel, T., Gessier, F., et al. (2014) · Cancer Research · doi:10.1158/1538-7445.am2014-1797 · Cited by 4 · see citing works
Self-citationFerretti, S., Berger, M., Rebmann, R., Santacroce, F., Sterker, D., Jensen, M. R., Masuya, K., & Jeay, S. (2014) · Cancer Research · doi:10.1158/1538-7445.am2014-4638 · Cited by 3 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Bouaoun, L., Sonkin, D., Ardin, M., Hollstein, M., Byrnes, G., Zavadil, J., & Olivier, M. (2016) · Human Mutation · doi:10.1002/humu.23035 · Cited by 730 · see citing works
Mutational processes shape the landscape of TP53 mutations in human cancer
Giacomelli, A. O., Yang, X., Lintner, R. E., McFarland, J. M., Duby, M., Kim, J., Howard, T. P., Takeda, D. Y., Ly, S. H., Kim, E., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0204-y · Cited by 556 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
Clinical Overview of MDM2/X-Targeted Therapies
Burgess, A., Chia, K. M., Haupt, S., Thomas, D., Haupt, Y., & Lim, E. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00007 · Cited by 315 · see citing works
The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice
Townsend, E. C., Murakami, M. A., Christodoulou, A., Christie, A. L., Köster, J., DeSouza, T. A., Morgan, E. A., Kallgren, S. P., Liu, H., Wu, S.-C., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.03.008 · Cited by 295 · see citing works
Self-citationHolzer, P., Masuya, K., Furet, P., Kallen, J., Valat-Stachyra, T., Ferretti, S., Berghausen, J., Bouisset-Leonard, M., Buschmann, N., Pissot-Soldermann, C., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00810 · Cited by 203 · see citing works
Self-citationDrug sensitivity of single cancer cells is predicted by changes in mass accumulation rate
Stevens, M. M., Maire, C. L., Chou, N., Murakami, M. A., Knoff, D. S., Kikuchi, Y., Kimmerling, R. J., Liu, H., Haidar, S., Calistri, N. L., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3697 · Cited by 106 · see citing works
Self-citationSmall-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives
Fang, Y., Liao, G., & Yu, B. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.01.003 · Cited by 106 · see citing works
Reis, B., Jukofsky, L., Chen, G., Martinelli, G., Zhong, H., So, W. V., Dickinson, M. J., Drummond, M., Assouline, S., Hashemyan, M., et al. (2016) · Haematologica · doi:10.3324/haematol.2015.139717 · Cited by 91 · see citing works
Jeay, S., Ferretti, S., Holzer, P., Fuchs, J., Chapeau, E. A., Wartmann, M., Sterker, D., Romanet, V., Murakami, M., Kerr, G., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0338 · Cited by 87 · see citing works
Self-citationChapeau, E. A., Gembarska, A., Durand, E. Y., Mandon, E., Estadieu, C., Romanet, V., Wiesmann, M., Tiedt, R., Lehar, J., de Weck, A., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620262114 · Cited by 64 · see citing works
Self-citationInhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097
Weisberg, E., Halilovic, E., Cooke, V. G., Nonami, A., Ren, T., Sanda, T., Simkin, I., Yuan, J., Antonakos, B., Barys, L., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0429 · Cited by 56 · see citing works
Self-citationKocik, J., Machula, M., Wisniewska, A., Surmiak, E., Holak, T. A., & Skalniak, L. (2019) · Cancers · doi:10.3390/cancers11071014 · Cited by 46 · see citing works
Wang, H. Q., Halilovic, E., Li, X., Liang, J., Cao, Y., Rakiec, D. P., Ruddy, D. A., Jeay, S., Wuerthner, J. U., Timple, N., et al. (2017) · eLife · doi:10.7554/elife.17137 · Cited by 45 · see citing works
Self-citation
- Authors
- Jeay, S., Gaulis, S., Ferretti, S., Bitter, H., Ito, M., Valat, T., Murakami, M., Ruetz, S., Guthy, D. A., Rynn, C., Jensen, M. R., Wiesmann, M., Kallen, J., Furet, P., Gessier, F., Holzer, P., Masuya, K., Würthner, J., Halilovic, E., Hofmann, F., Sellers, W. R., & Graus Porta, D.
- Affiliations
- Novartis (Switzerland) (CH)
- Novartis Institutes for BioMedical Research (CH)
- Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
- Corresponding author
- Jeay, Sébastien
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2015-05-12
- Volume
- 4
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4468608
- OpenAlex
- W2176265001
- Cited by
- 85
- References
- 56
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 9 · 2022: 3 · 2021: 12 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 12 · 2016: 10 · 2015: 5
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-11-17)
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Novartis
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- p53 target genes, predictive gene signature, patient selection biomarkers, cell line sensitivity, patient-derived xenografts, drug response prediction
- MeSH terms
- Humans, Isoquinolines, Neoplasms, Piperazines, Biomarkers, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Patient Selection, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Fluorescence Resonance Energy Transfer, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
