دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: MEK inhibition causes BIM stabilization and increased sensitivity to BCL-2 family member inhibitors in RAS-MAPK-mutated neuroblastoma.
المؤلفون: Eleveld TF; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.; Department of Oncogenomics, Amsterdam UMC, Amsterdam, Netherlands., Vernooij L; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Schild L; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Koopmans B; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Alles LK; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Ebus ME; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Dandis R; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., van Tinteren H; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Caron HN; Hoffmann-La Roche, Basel, Switzerland., Koster J; Department of Oncogenomics, Amsterdam UMC, Amsterdam, Netherlands., van Noesel MM; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Tytgat GAM; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Eising S; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Versteeg R; Department of Oncogenomics, Amsterdam UMC, Amsterdam, Netherlands., Dolman MEM; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia.; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia., Molenaar JJ; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.; Department of Pharmaceutical sciences, Utrecht University, Utrecht, Netherlands.
المصدر: Frontiers in oncology [Front Oncol] 2023 Feb 21; Vol. 13, pp. 1130034. Date of Electronic Publication: 2023 Feb 21 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101568867 Publication Model: eCollection Cited Medium: Print ISSN: 2234-943X (Print) Linking ISSN: 2234943X NLM ISO Abbreviation: Front Oncol Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [Lausanne : Frontiers Research Foundation]
مستخلص: Introduction: 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.
Competing Interests: HC is employed by Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Eleveld, Vernooij, Schild, Koopmans, Alles, Ebus, Dandis, van Tinteren, Caron, Koster, van Noesel, Tytgat, Eising, Versteeg, Dolman and Molenaar.)
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فهرسة مساهمة: Keywords: MEK; b-cell lymphoma 2 (BCL-2); navitoclax (ABT-263, PubChem CID: 24978538); neuroblastoma; pediatric cancer; synergy; trametinib (PubChem CID: 11707110); venetoclax (ABT-199, PubChem CID: 49846579)
تواريخ الأحداث: Date Created: 20230310 Latest Revision: 20230311
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9990464
DOI: 10.3389/fonc.2023.1130034
PMID: 36895472
قاعدة البيانات: MEDLINE
الوصف
تدمد:2234-943X
DOI:10.3389/fonc.2023.1130034