دورية أكاديمية
MEK inhibition causes BIM stabilization and increased sensitivity to BCL-2 family member inhibitors in RAS-MAPK-mutated neuroblastoma.
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.) |
References: | J Clin Oncol. 2014 Sep 1;32(25):2727-34. (PMID: 25071110) Eur J Cancer. 2009 Jan;45(2):228-47. (PMID: 19097774) Mol Cancer Ther. 2021 Jun;20(6):1161-1172. (PMID: 33850004) Children (Basel). 2019 Feb 11;6(2):. (PMID: 30754710) Cancer Res. 2012 May 15;72(10):2565-77. (PMID: 22589275) Cancer Res. 2008 May 1;68(9):3421-8. (PMID: 18451170) Cell Death Discov. 2022 Apr 7;8(1):172. (PMID: 35393436) Nature. 2012 Feb 22;483(7391):589-93. (PMID: 22367537) JAMA. 2012 Mar 14;307(10):1062-71. (PMID: 22416102) Oncogene. 2008 Dec 4;27(57):7150-61. (PMID: 18806830) Science. 2018 Dec 7;362(6419):1165-1170. (PMID: 30523111) Cancer Cell. 2005 Mar;7(3):227-38. (PMID: 15766661) Oncotarget. 2016 May 10;7(19):27946-58. (PMID: 27056887) BMC Cancer. 2016 Feb 13;16:97. (PMID: 26874859) Cancer Cell. 2016 Feb 8;29(2):159-72. (PMID: 26859456) J Clin Invest. 2008 Nov;118(11):3651-9. (PMID: 18949058) Pediatr Blood Cancer. 2008 Jun;50(6):1181-9. (PMID: 18085673) N Engl J Med. 2012 Jul 12;367(2):107-14. (PMID: 22663011) Br J Cancer. 2020 May;122(10):1544-1551. (PMID: 32203216) Sci Rep. 2020 Dec 31;10(1):22432. (PMID: 33384420) Nat Med. 2013 Feb;19(2):202-8. (PMID: 23291630) J Biomol Screen. 2014 Jun;19(5):817-21. (PMID: 24492921) Lancet Oncol. 2010 Dec;11(12):1149-59. (PMID: 21094089) Nat Genet. 2013 Mar;45(3):279-84. (PMID: 23334666) J Clin Oncol. 2013 Feb 1;31(4):482-9. (PMID: 23248257) Nat Genet. 2013 Jan;45(1):12-7. (PMID: 23202128) Nat Genet. 2015 Aug;47(8):872-7. (PMID: 26121086) Cell Death Differ. 2005 Aug;12(8):1008-14. (PMID: 15947788) Cancer Cell. 2013 Jan 14;23(1):121-8. (PMID: 23245996) Nature. 2013 Sep 12;501(7466):232-6. (PMID: 23934108) Oncotarget. 2014 Sep 15;5(17):7936-44. (PMID: 25277205) Nat Genet. 2015 Aug;47(8):864-71. (PMID: 26121087) Br J Cancer. 2012 Apr 10;106(8):1386-94. (PMID: 22415236) Neurooncol Adv. 2019 May 28;1(1):vdz004. (PMID: 32642647) PLoS Genet. 2016 Dec 20;12(12):e1006501. (PMID: 27997549) Clin Cancer Res. 2014 Sep 1;20(17):4520-31. (PMID: 25013123) Cancers (Basel). 2021 Mar 23;13(6):. (PMID: 33807122) Clin Cancer Res. 2010 Feb 15;16(4):1108-18. (PMID: 20145180) J Pediatr Surg. 2019 Mar;54(3):383-389. (PMID: 30305231) Pediatr Blood Cancer. 2020 Apr;67(4):e28061. (PMID: 31736229) Eur J Cancer. 2012 Nov;48(16):3093-103. (PMID: 22366560) Mol Cancer Ther. 2013 Jun;12(6):853-64. (PMID: 23475955) Cell Death Differ. 2010 May;17(5):872-82. (PMID: 19893570) |
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 |
كن أول من يترك تعليقا!