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MEK inhibition is a promising therapeutic strategy for MLL -rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations

2016; Impact Journals LLC; Volume: 8; Issue: 9 Linguagem: Inglês

10.18632/oncotarget.11730

1949-2553

Mark Kerstjens, Emma M. C. Driessen, Merel Willekes, Sandra S. Pinhanços, Pauline Schneider, Rob Pieters, Ronald W. Stam,

Acute Lymphoblastic Leukemia research

// Mark Kerstjens 1, * , Emma M.C. Driessen 1, * , Merel Willekes 1 , Sandra S. Pinhanços 1 , Pauline Schneider 1 , Rob Pieters 1, 2 , Ronald W. Stam 1 1 Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands 2 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands * These authors have contributed equally to this work Correspondence to: Ronald W. Stam, email: r.stam@erasmusmc.nl Keywords: MLL-rearrangements, RAS-pathway, leukemia, MEK inhibitors Received: May 31, 2016 Accepted: August 13, 2016 Published: August 31, 2016 ABSTRACT Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS -mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS -mutant MLL -rearranged infant ALL cells in vitro . While all RAS -mutant samples were sensitive to MEK inhibitors, we found both sensitive and resistant samples among RAS -wildtype cases. We confirmed enhanced RAS pathway signaling in RAS -mutant samples, but found no apparent downstream over-activation in the wildtype samples. However, we did confirm that MEK inhibitors reduced p-ERK levels, and induced apoptosis in the RAS -mutant MLL -rearranged ALL cells. Finally, we show that MEK inhibition synergistically enhances prednisolone sensitivity, both in RAS -mutant and RAS -wildtype cells. In conclusion, MEK inhibition represents a promising therapeutic strategy for MLL -rearranged ALL patients harboring RAS mutations, while patients without RAS mutations may benefit through prednisolone sensitization.