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MEK inhibitors overcome resistance to BET inhibition across a number of solid and hematologic cancers.
Wyce, Anastasia; Matteo, Jeanne J; Foley, Shawn W; Felitsky, Daniel J; Rajapurkar, Satyajit R; Zhang, Xi-Ping; Musso, Melissa C; Korenchuk, Susan; Karpinich, Natalie O; Keenan, Kathryn M; Stern, Melissa; Mathew, Lijoy K; McHugh, Charles F; McCabe, Michael T; Tummino, Peter J; Kruger, Ryan G; Carpenter, Christopher; Barbash, Olena.
Afiliación
  • 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.
  • Kruger RG; Janssen Pharmaceuticals, Spring House, Montgomery, 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.
Oncogenesis ; 7(4): 35, 2018 Apr 20.
Article en En | MEDLINE | ID: mdl-29674704
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Oncogenesis Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Oncogenesis Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos