title: A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097.
abstract: 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.
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jeay
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Swann
authors.initials: S
authors.lastname: Gaulis
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ferretti
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Hans
authors.initials: H
authors.lastname: Bitter
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Moriko
authors.initials: M
authors.lastname: Ito
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Valat
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruetz
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Guthy
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rynn
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jensen
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.affiliation: Center of Proteomic Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Kallen
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Gessier
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Holzer
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Masuya
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Würthner
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Ensar
authors.initials: E
authors.lastname: Halilovic
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Graus Porta
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D045744:Cell Line, Tumor; D031541:Fluorescence Resonance Energy Transfer; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007546:Isoquinolines; C000602644:NVP-CGM097; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: HDM2; human; human biology; medicine; p53; predictive signature; translational oncology