title: FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor.
abstract: Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective fibroblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line-sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the first time, we report oncogenic FGFR1 amplification in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identified predictors of sensitivity.
  
  
  CONCLUSIONS
  The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefit the most from any given drug. To this end, we have integrated the molecular profiles for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specific patient selection biomakers in the clinical trials for NVP-BGJ398.
authors.affiliation: Global Discovery Chemistry, 2Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Vito
authors.initials: V
authors.lastname: Guagnano
authors.forename: Audrey
authors.initials: A
authors.lastname: Kauffmann
authors.forename: Simon
authors.initials: S
authors.lastname: Wöhrle
authors.forename: Christelle
authors.initials: C
authors.lastname: Stamm
authors.forename: Moriko
authors.initials: M
authors.lastname: Ito
authors.forename: Louise
authors.initials: L
authors.lastname: Barys
authors.forename: Astrid
authors.initials: A
authors.lastname: Pornon
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilson
authors.forename: Vincent
authors.initials: V
authors.lastname: Bordas
authors.forename: Mickaël
authors.initials: M
authors.lastname: Le Douget
authors.forename: L Alex
authors.initials: LA
authors.lastname: Gaither
authors.forename: Jason
authors.initials: J
authors.lastname: Borawski
authors.forename: John E
authors.initials: JE
authors.lastname: Monahan
authors.forename: Kavitha
authors.initials: K
authors.lastname: Venkatesan
authors.forename: Thomas
authors.initials: T
authors.lastname: Brümmendorf
authors.forename: David M
authors.initials: DM
authors.lastname: Thomas
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Diana
authors.initials: D
authors.lastname: Graus-Porta
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005784:Gene Amplification / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; C568950:infigratinib; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2