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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.
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 Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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
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 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
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 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
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