TY - JOUR
T1 - Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways
AU - Butler, Miriam
AU - Vervoort, Britt M.T.
AU - van Ingen Schenau, Dorette S.
AU - Jongeneel, Lieneke
AU - van der Zwet, Jordy C.G.
AU - Marke, René
AU - Meijerink, Jules P.P.
AU - Scheijen, Blanca
AU - van der Meer, Laurens T.
AU - van Leeuwen, Frank N.
N1 - Copyright © 2022 Butler, Vervoort, van Ingen Schenau, Jongeneel, van der Zwet, Marke, Meijerink, Scheijen, van der Meer and van Leeuwen.
PY - 2022/9/2
Y1 - 2022/9/2
N2 - Although long-term survival in pediatric acute lymphoblastic leukemia (ALL) currently exceeds 90%, some subgroups, defined by specific genomic aberrations, respond poorly to treatment. We previously reported that leukemias harboring deletions or mutations affecting the B-cell transcription factor IKZF1 exhibit a tumor cell intrinsic resistance to glucocorticoids (GCs), one of the cornerstone drugs used in the treatment of ALL. Here, we identified increased activation of both AKT and ERK signaling pathways as drivers of GC resistance in IKZF1-deficient leukemic cells. Indeed, combined pharmacological inhibition of AKT and ERK signaling effectively reversed GC resistance in IKZF1-deficient leukemias. As inhibitors for both pathways are under clinical investigation, their combined use may enhance the efficacy of prednisolone-based therapy in this high-risk patient group.
AB - Although long-term survival in pediatric acute lymphoblastic leukemia (ALL) currently exceeds 90%, some subgroups, defined by specific genomic aberrations, respond poorly to treatment. We previously reported that leukemias harboring deletions or mutations affecting the B-cell transcription factor IKZF1 exhibit a tumor cell intrinsic resistance to glucocorticoids (GCs), one of the cornerstone drugs used in the treatment of ALL. Here, we identified increased activation of both AKT and ERK signaling pathways as drivers of GC resistance in IKZF1-deficient leukemic cells. Indeed, combined pharmacological inhibition of AKT and ERK signaling effectively reversed GC resistance in IKZF1-deficient leukemias. As inhibitors for both pathways are under clinical investigation, their combined use may enhance the efficacy of prednisolone-based therapy in this high-risk patient group.
KW - AKT
KW - ERK
KW - glucocorticoids
KW - IKZF1
KW - leukemia
KW - therapy resistance
UR - http://www.scopus.com/inward/record.url?scp=85138203874&partnerID=8YFLogxK
U2 - 10.3389/fonc.2022.905665
DO - 10.3389/fonc.2022.905665
M3 - Article
C2 - 36119546
AN - SCOPUS:85138203874
SN - 2234-943X
VL - 12
SP - 905665
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 905665
ER -