In:
Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-2-21)
Abstract:
Mutations affecting the RAS-MAPK pathway occur frequently in relapsed neuroblastoma tumors and are associated with response to MEK inhibition in vitro . However, these inhibitors alone do not lead to tumor regression in vivo , indicating the need for combination therapy. Methods and results Via high-throughput combination screening, we identified that the MEK inhibitor trametinib can be combined with BCL-2 family member inhibitors, to efficiently inhibit growth of neuroblastoma cell lines with RAS-MAPK mutations. Suppressing the RAS-MAPK pathway with trametinib led to an increase in pro-apoptotic BIM, resulting in more BIM binding to anti-apoptotic BCL-2 family members. By favoring the formation of these complexes, trametinib treatment enhances sensitivity to compounds targeting anti-apoptotic BCL-2 family members. In vitro validation studies confirmed that this sensitizing effect is dependent on an active RAS-MAPK pathway. In vivo combination of trametinib with BCL-2 inhibitors led to tumor inhibition in NRAS -mutant and NF1 -deleted xenografts. Conclusion Together, these results show that combining MEK inhibition with BCL-2 family member inhibition could potentially improve therapeutic outcomes for RAS-MAPK-mutated neuroblastoma patients.
Type of Medium:
Online Resource
ISSN:
2234-943X
DOI:
10.3389/fonc.2023.1130034
DOI:
10.3389/fonc.2023.1130034.s001
DOI:
10.3389/fonc.2023.1130034.s002
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2023
detail.hit.zdb_id:
2649216-7
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