دورية أكاديمية
MEK inhibitors overcome resistance to BET inhibition across a number of solid and hematologic cancers.
العنوان: | MEK inhibitors overcome resistance to BET inhibition across a number of solid and hematologic cancers. |
---|---|
المؤلفون: | Wyce A; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Matteo JJ; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Foley SW; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Felitsky DJ; Target Sciences, GlaxoSmithKline, Upper Merion, PA, USA., Rajapurkar SR; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Zhang XP; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Musso MC; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Korenchuk S; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Karpinich NO; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Keenan KM; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Stern M; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Mathew LK; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., McHugh CF; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., McCabe MT; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Tummino PJ; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA.; Janssen Pharmaceuticals, Spring House, Montgomery, PA, USA., Kruger RG; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Carpenter C; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Barbash O; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA. olena.x.barbash@gsk.com. |
المصدر: | Oncogenesis [Oncogenesis] 2018 Apr 20; Vol. 7 (4), pp. 35. Date of Electronic Publication: 2018 Apr 20. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101580004 Publication Model: Electronic Cited Medium: Print ISSN: 2157-9024 (Print) Linking ISSN: 21579024 NLM ISO Abbreviation: Oncogenesis Subsets: PubMed not MEDLINE |
أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Group |
مستخلص: | BET inhibitors exhibit broad activity in cancer models, making predictive biomarkers challenging to define. Here we investigate the biomarkers of activity of the clinical BET inhibitor GSK525762 (I-BET; I-BET762) across cancer cell lines and demonstrate that KRAS mutations are novel resistance biomarkers. This finding led us to combine BET with RAS pathway inhibition using MEK inhibitors to overcome resistance, which resulted in synergistic effects on growth and survival in RAS pathway mutant models as well as a subset of cell lines lacking RAS pathway mutations. GSK525762 treatment up-regulated p-ERK1/2 levels in both RAS pathway wild-type and mutant cell lines, suggesting that MEK/ERK pathway activation may also be a mechanism of adaptive BET inhibitor resistance. Importantly, gene expression studies demonstrated that the BET/MEK combination uniquely sustains down-regulation of genes associated with mitosis, leading to prolonged growth arrest that is not observed with either single agent therapy. These studies highlight a potential to enhance the clinical benefit of BET and MEK inhibitors and provide a strong rationale for clinical evaluation of BET/MEK combination therapies in cancer. |
References: | Oncotarget. 2013 Dec;4(12):2419-29. (PMID: 24293458) Nature. 2011 Oct 02;478(7370):529-33. (PMID: 21964340) Cell Rep. 2016 Aug 2;16(5):1273-1286. (PMID: 27452461) Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517) BMC Bioinformatics. 2011 Aug 04;12:322. (PMID: 21816037) Mol Cancer Ther. 2016 Sep;15(9):2030-41. (PMID: 27406984) Cancer Discov. 2018 Jan;8(1):59-73. (PMID: 29054992) Mol Cancer Ther. 2016 Jun;15(6):1217-26. (PMID: 26983878) Nature. 2014 Oct 9;514(7521):247-51. (PMID: 25119042) Clin Cancer Res. 2017 Apr 15;23 (8):2027-2037. (PMID: 27678457) Adv Enzyme Regul. 1984;22:27-55. (PMID: 6382953) Epigenomics. 2015;7(3):487-501. (PMID: 26077433) Discov Med. 2014 May;17(95):275-83. (PMID: 24882719) Cell Rep. 2015 Apr 21;11(3):390-404. (PMID: 25865888) Nature. 2015 Sep 24;525(7570):543-547. (PMID: 26367798) Bioinformatics. 2004 Feb 12;20(3):307-15. (PMID: 14960456) Nature. 2010 Dec 23;468(7327):1119-23. (PMID: 21068722) Nucleic Acids Res. 2015 Apr 20;43(7):e47. (PMID: 25605792) Oncotarget. 2016 Jan 19;7(3):2545-54. (PMID: 26575423) Nature. 2015 Sep 24;525(7570):538-42. (PMID: 26367796) Nature. 2013 Sep 12;501(7466):232-6. (PMID: 23934108) Cancer Cell. 2015 Jun 8;27(6):837-51. (PMID: 26058079) Nature. 2016 Jan 21;529(7586):413-417. (PMID: 26735014) Nat Methods. 2015 Feb;12(2):115-21. (PMID: 25633503) Nature. 2012 Mar 28;483(7391):603-7. (PMID: 22460905) Clin Cancer Res. 2011 Mar 1;17(5):989-1000. (PMID: 21245089) J Thorac Oncol. 2016 Aug;11(8):1233-1241. (PMID: 27133774) |
تواريخ الأحداث: | Date Created: 20180421 Latest Revision: 20201001 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC5908790 |
DOI: | 10.1038/s41389-018-0043-9 |
PMID: | 29674704 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2157-9024 |
---|---|
DOI: | 10.1038/s41389-018-0043-9 |