Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways
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 IK...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.905665/full |
| _version_ | 1811184729746046976 |
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| author | Miriam Butler Miriam Butler Britt M.T. Vervoort Dorette S. van Ingen Schenau Lieneke Jongeneel Jordy C.G. van der Zwet René Marke Jules P.P. Meijerink Blanca Scheijen Blanca Scheijen Laurens T. van der Meer Frank N. van Leeuwen |
| author_facet | Miriam Butler Miriam Butler Britt M.T. Vervoort Dorette S. van Ingen Schenau Lieneke Jongeneel Jordy C.G. van der Zwet René Marke Jules P.P. Meijerink Blanca Scheijen Blanca Scheijen Laurens T. van der Meer Frank N. van Leeuwen |
| author_sort | Miriam Butler |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T13:17:27Z |
| format | Article |
| id | doaj.art-bd62010cd4ac4cb38d96197bfa9e66ae |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T13:17:27Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-bd62010cd4ac4cb38d96197bfa9e66ae2022-12-22T04:22:22ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-09-011210.3389/fonc.2022.905665905665Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathwaysMiriam Butler0Miriam Butler1Britt M.T. Vervoort2Dorette S. van Ingen Schenau3Lieneke Jongeneel4Jordy C.G. van der Zwet5René Marke6Jules P.P. Meijerink7Blanca Scheijen8Blanca Scheijen9Laurens T. van der Meer10Frank N. van Leeuwen11Princess Maxima Center for Pediatric Oncology, Utrecht, NetherlandsLaboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, NetherlandsLaboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, NetherlandsDepartment of Pathology, Radboud University Medical Center, Nijmegen, NetherlandsRadboud Institute for Molecular Life Sciences, Nijmegen, NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, NetherlandsPrincess Maxima Center for Pediatric Oncology, Utrecht, NetherlandsAlthough 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.https://www.frontiersin.org/articles/10.3389/fonc.2022.905665/fullleukemiaglucocorticoidsIKZF1therapy resistanceAKTERK |
| spellingShingle | Miriam Butler Miriam Butler Britt M.T. Vervoort Dorette S. van Ingen Schenau Lieneke Jongeneel Jordy C.G. van der Zwet René Marke Jules P.P. Meijerink Blanca Scheijen Blanca Scheijen Laurens T. van der Meer Frank N. van Leeuwen Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways Frontiers in Oncology leukemia glucocorticoids IKZF1 therapy resistance AKT ERK |
| title | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
| title_full | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
| title_fullStr | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
| title_full_unstemmed | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
| title_short | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
| title_sort | reversal of ikzf1 induced glucocorticoid resistance by dual targeting of akt and erk signaling pathways |
| topic | leukemia glucocorticoids IKZF1 therapy resistance AKT ERK |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.905665/full |
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