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Ras pathway mutations are highly prevalent in relapsed childhood acute lymphoblastic leukaemia, may act as relapse-drivers and confer sensitivity to MEK inhibition

Julie Irving, Elizabeth Matheson, Lynne Minto, Helen Blair, Marian Case, Christina Halsey, Isabella Swidenbank, Frida Ponthan, Renate Kirschner-Schwabe, Stefanie Groeneveld-Krentz, Jana Hof, James Allan, Christine Harrison, Josef Vormoor, Arend von Stackelberg and Cornelia Eckert
This article has an Erratum 125(5):890

Key points

  • RAS pathway mutations are prevalent in relapsed childhood ALL and KRAS mutations are associated with a poorer overall survival.

  • RAS pathway mutations confer sensitivity to MEK inhibitors.

Abstract

For most children who relapse with acute lymphoblastic leukaemia, 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 (ClinicalTrials.gov identifier: 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, 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 wildtype but 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 MEK1/2 inhibitor, selumetinib (AZD6244, ARRY-142886) showed significant differential sensitivity in Ras pathway mutated ALL compared to wild type cells both in vitro and in a orthotopic xenograft model engrafted with primary ALL and in the latter, reduced RAS mutated CNS leukaemia. Given these data, clinical evaluation of selumetinib may be warranted for Ras pathway mutated relapsed ALL.

  • Submitted April 10, 2014.
  • Accepted August 26, 2014.