title: Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition.
abstract: For most children who relapse with acute lymphoblastic leukemia (ALL), the prognosis is poor, and there is a need for novel therapies to improve outcome. We screened samples from children with B-lineage ALL entered into the ALL-REZ BFM 2002 clinical trial (www.clinicaltrials.gov, #NCT00114348) for somatic mutations activating the Ras pathway (KRAS, NRAS, FLT3, and PTPN11) and showed mutation to be highly prevalent (76 from 206). Clinically, they were associated with high-risk features including early relapse, central nervous system (CNS) involvement, and specifically for NRAS/KRAS mutations, chemoresistance. KRAS mutations were associated with a reduced overall survival. Mutation screening of the matched diagnostic samples found many to be wild type (WT); however, by using more sensitive allelic-specific assays, low-level mutated subpopulations were found in many cases, suggesting that they survived up-front therapy and subsequently emerged at relapse. Preclinical evaluation of the mitogen-activated protein kinase kinase 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) showed significant differential sensitivity in Ras pathway-mutated ALL compared with WT cells both in vitro and in an orthotopic xenograft model engrafted with primary ALL; in the latter, reduced RAS-mutated CNS leukemia. Given these data, clinical evaluation of selumetinib may be warranted for Ras pathway-mutated relapsed ALL.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Julie
authors.initials: J
authors.lastname: Irving
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Matheson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Lynne
authors.initials: L
authors.lastname: Minto
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Helen
authors.initials: H
authors.lastname: Blair
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Marian
authors.initials: M
authors.lastname: Case
authors.affiliation: Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom;
authors.forename: Christina
authors.initials: C
authors.lastname: Halsey
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; and.
authors.forename: Isabella
authors.initials: I
authors.lastname: Swidenbank
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Frida
authors.initials: F
authors.lastname: Ponthan
authors.affiliation: Charité - Universitätsmedizin Berlin, Department of Paediatric Oncology/Haematology, Berlin, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Kirschner-Schwabe
authors.affiliation: Charité - Universitätsmedizin Berlin, Department of Paediatric Oncology/Haematology, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Groeneveld-Krentz
authors.affiliation: Charité - Universitätsmedizin Berlin, Department of Paediatric Oncology/Haematology, Berlin, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Hof
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: James
authors.initials: J
authors.lastname: Allan
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Christine
authors.initials: C
authors.lastname: Harrison
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Josef
authors.initials: J
authors.lastname: Vormoor
authors.affiliation: Charité - Universitätsmedizin Berlin, Department of Paediatric Oncology/Haematology, Berlin, Germany.
authors.forename: Arend
authors.initials: A
authors.lastname: von Stackelberg
authors.affiliation: Charité - Universitätsmedizin Berlin, Department of Paediatric Oncology/Haematology, Berlin, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002648:Child; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005787:Gene Frequency; D011905:Genes, ras; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases