Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition

Abstract

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 mitogenactivated protein kinase kinase inhibitors.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. (Blood. 2014;124(23):3420-3430)

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

“…We retrieved the expected pattern of mutations (supplemental Figure 1; supplemental Table 3) with frequent events in KRAS (13 of 25) and TP53 (10 of 25), consistent with previous reports. 33,34 On average, 74% of single nucleotide variants and insertions/deletions were conserved between the primary diagnostic samples and PDXs ( Figure 1B; supplemental Figure 1). Oncogenic translocations were always maintained.…”

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

“…These included activating mutations in KRAS in 11 of 55 (20%) cases (7 of 22, 32% B-precursor ALL; 4 of 33, 12% T-ALL), gain-of-function mutations in NRAS in 13 of 55 (24%) cases (4 of 22, 18% B-precursor ALL; 9 of 33, 27% T-ALL), and one activating mutation in the PTPN11 (PTPN11 G503R) phosphatase gene previously reported in Noonan syndrome (28,29) (Fig. 1C, (18,30,31) and differs from the results obtained from the analysis of unselected pediatric ALLs, which showed a markedly lower frequency of activating mutations in NRAS (5 of 41, 12%) and KRAS (0 of 41, 0%) (Fisher's exact test P < 0.005), suggesting that aberrant MAPK signaling could be a prominent driver oncogenic mechanism in high-risk ALL. However, we noted that although most cases with NRAS and KRAS mutations present at diagnosis were recovered at relapse (12 of 24, 50%) and others showed emergence of a different RAS mutant allele (1 of 24, 4%) or of new RAS mutant clones at relapse (6 of 24, 25%), some patients with NRAS and KRAS mutations at diagnosis relapsed at the expense of RAS wild-type clones (5 of 24, 21%).…”

Genetic drivers of vulnerability and resistance in relapsed acute lymphoblastic leukemia

“…In addition to previously described relapse-associated mutations and CN changes, the authors also noted enrichment of mutations in genes involved in MAP kinase signaling (8,12), including NRAS (24%), KRAS (20%), and PTPN11 (4.5%) mutations. Altogether, 48.5% of all cases had a mutation known to activate MAP kinase signaling at relapse.…”

“…Moreover, given that the therapeutic studies described above were performed in T-ALL models, evaluation of these findings in the context of B-ALL will also be important. Finally, RAS mutations have also previously been linked to prednisolone resistance (15) as well, and the MEK inhibitor trametinib was shown in at least one study to be synergistic with prednisolone (12,16).…”

“…Moreover, given that the therapeutic studies described above were performed in T-ALL models, evaluation of these findings in the context of B-ALL will also be important. Finally, RAS mutations have also previously been linked to prednisolone resistance (15) as well, and the MEK inhibitor trametinib was shown in at least one study to be synergistic with prednisolone (12,16).Given these findings and the data here revealing collaborative cytotoxic effects of MTX and MEK inhibition, combining MEK inhibitors with conventional therapies may be important to evaluate clinically in the treatment of RAS-mutant ALL.The insights from this study and prior literature on the genomic analysis of relapsed ALL further highlights that, in most cases, relapse in ALL represents evolution from an ancestral clone present as a subclone at diagnosis. Furthermore, it is clear that relapses in pediatric ALL are not associated with marked increases in genomic alterations.…”