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Ref Type

Journal Article

PMID

(36895472)

Authors

Eleveld TF, Vernooij L, Schild L, Koopmans B, Alles LK, Ebus ME, Dandis R, van Tinteren H, Caron HN, Koster J, van Noesel MM, Tytgat GAM, Eising S, Versteeg R, Dolman MEM, Molenaar JJ

Title

MEK inhibition causes BIM stabilization and increased sensitivity to BCL-2 family member inhibitors in RAS-MAPK-mutated neuroblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Frontiers in oncology	13		2023	1130034	Front Oncol

URL

Abstract Text

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.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.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.

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS act mut	neuroblastoma	predicted - sensitive	Trametinib + Venetoclax	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to Venclexta (venetoclax), resulting in reduced cell viability in culture, and the combination treatment resulted in tumor growth inhibition with 2/6 partial responses and 3/6 with stable disease in cell line xenograft models (PMID: 36895472).	36895472
NRAS act mut	neuroblastoma	predicted - sensitive	Navitoclax + Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to Navitoclax (ABT-263), resulting in reduced cell viability in culture, and the combination treatment resulted in tumor regression in cell line xenograft models (6/6 partial responses) (PMID: 36895472).	36895472
ALK act mut	neuroblastoma	predicted - sensitive	Trametinib + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an ALK activating mutation to Venclexta (venetoclax), resulting in reduced cell viability in culture (PMID: 36895472).	36895472
ALK act mut	neuroblastoma	predicted - sensitive	S63845 + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an ALK activating mutation to S63845 (MIK655), resulting in reduced cell viability in culture (PMID: 36895472).	36895472
ALK act mut	neuroblastoma	predicted - sensitive	Navitoclax + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Mekinist (trametinib) sensitized neuroblastoma cell lines harboring ALK activating mutations to Navitoclax (ABT-263), resulting in reduced cell viability in culture (PMID: 36895472).	36895472
NRAS act mut	neuroblastoma	predicted - sensitive	S63845 + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to S63845 (MIK655), resulting in reduced cell viability in culture (PMID: 36895472).	36895472

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