Irving Julie, Matheson Elizabeth, Minto Lynne, Blair Helen, Case Marian, Halsey Christina, Swidenbank Isabella, Ponthan Frida, Kirschner-Schwabe Renate, Groeneveld-Krentz Stefanie, Hof Jana, Allan James, Harrison Christine, Vormoor Josef, von Stackelberg Arend, Eckert Cornelia
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom;
Blood. 2014 Nov 27;124(23):3420-30. doi: 10.1182/blood-2014-04-531871. Epub 2014 Sep 24.
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.
对于大多数急性淋巴细胞白血病（ALL）复发的儿童来说，预后很差，需要新的疗法来改善结局。我们对参加ALL-REZ BFM 2002临床试验（www.clinicaltrials.gov，#NCT00114348）的B系ALL儿童样本进行了筛查，以寻找激活Ras通路的体细胞突变（KRAS、NRAS、FLT3和PTPN11），结果显示突变非常普遍（206例中有76例）。临床上，这些突变与高风险特征相关，包括早期复发、中枢神经系统（CNS）受累，特别是NRAS/KRAS突变与化疗耐药有关。KRAS突变与总生存期缩短相关。对匹配的诊断样本进行突变筛查发现，许多样本为野生型（WT）；然而，通过使用更敏感的等位基因特异性检测方法，在许多病例中发现了低水平的突变亚群，这表明它们在前期治疗中存活下来，并在复发时出现。丝裂原活化蛋白激酶激酶1/2抑制剂司美替尼（AZD6244，ARRY-142886）的临床前评估显示，与WT细胞相比，Ras通路突变的ALL在体外和原发性ALL植入的原位异种移植模型中均表现出显著的差异敏感性；在后者中，RAS突变的中枢神经系统白血病减少。鉴于这些数据，司美替尼可能有必要对Ras通路突变的复发ALL进行临床评估。
