TY - JOUR
T1 - MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations
AU - Kerstjens, Mark
AU - Driessen, Emma M.C.
AU - Willekes, Merel
AU - Pinhanços, Sandra S.
AU - Schneider, Pauline
AU - Pieters, Rob
AU - Stam, Ronald W.
N1 - Funding Information:
This work was financially supported by research funding from KIKA (Kinderen Kankervrij). Furthermore, R.W. Stam was financially supported by the Dutch Cancer Society (KWF Kankerbestrijding).
PY - 2017
Y1 - 2017
N2 - 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 RASmutant 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 RASmutant 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.
AB - 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 RASmutant 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 RASmutant 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.
KW - Leukemia
KW - MEK inhibitors
KW - MLL-rearrangements
KW - RAS-pathway
UR - http://www.scopus.com/inward/record.url?scp=85014078831&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.11730
DO - 10.18632/oncotarget.11730
M3 - Article
AN - SCOPUS:85014078831
SN - 1949-2553
VL - 8
SP - 14835
EP - 14846
JO - Oncotarget
JF - Oncotarget
IS - 9
ER -