title: The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas.
abstract: The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in squamous cell carcinoma of the head and neck (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from eight patients with HNSCC [four HPV-serotype16 (HPV16)-positive]. HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, Western blotting, and immunohistochemistry (IHC). Rigosertib had potent antiproliferative effects on 11 of 16 HPV(-) HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in three of eight HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA-activating event (amplification or mutation) and a p53-inactivating event (either HPV16- or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV(+) and HPV(-) HNSCCs, focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient, for rigosertib sensitivity.
authors.affiliation: Corresponding Author: Antonio Jimeno, University of Colorado School of Medicine, MS8117, 12801 East 17th Avenue, Room L18-8101B, Aurora, CO 80045. Antonio.Jimeno@ucdenver.edu.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Anderson
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Keysar
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bowles
authors.forename: Magdalena J
authors.initials: MJ
authors.lastname: Glogowska
authors.forename: David P
authors.initials: DP
authors.lastname: Astling
authors.forename: J Jason
authors.initials: JJ
authors.lastname: Morton
authors.forename: Phuong
authors.initials: P
authors.lastname: Le
authors.forename: Adrian
authors.initials: A
authors.lastname: Umpierrez
authors.forename: Justin
authors.initials: J
authors.lastname: Eagles-Soukup
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Gan
authors.forename: Brian W
authors.initials: BW
authors.lastname: Vogler
authors.forename: Daniel
authors.initials: D
authors.lastname: Sehrt
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Takimoto
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.forename: Francois
authors.initials: F
authors.lastname: Wilhelm
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Frederick
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D006801:Humans; D009154:Mutation; D027383:Papillomaviridae / Q000187:drug effects; D030361:Papillomavirus Infections / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013450:Sulfones / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D005998:Glycine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013450:Sulfones; D000097869:Polo-Like Kinase 1; C507134:ON 01910; C484760:PIK3CA protein, human