title: Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma.
abstract: Purpose:Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition.Experimental Design:We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies.Results:Sensitivity to binimetinib and ribociclib was inversely related (r= -0.58,P= 0.009).MYCNamplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs.Conclusions:Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling.Clin Cancer Res; 23(7); 1785-96. ©2016 AACR.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Hart
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: JulieAnn
authors.initials: J
authors.lastname: Rader
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Pichai
authors.initials: P
authors.lastname: Raman
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Vandana
authors.initials: V
authors.lastname: Batra
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Mike R
authors.initials: MR
authors.lastname: Russell
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tsang
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Maria
authors.initials: M
authors.lastname: Gagliardi
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Lucy
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martinez
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Sudha
authors.initials: S
authors.lastname: Parasuraman
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Scott
authors.initials: S
authors.lastname: Delach
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Cole
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: Shiva
authors.initials: S
authors.lastname: Krupa
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: Malte
authors.initials: M
authors.lastname: Peters
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Giordano
authors.initials: G
authors.lastname: Caponigro
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. maris@email.chop.edu.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C581313:binimetinib