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Vena F, Jia R, Esfandiari A, et al. MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models. Oncotarget. 2018;9(14):11592-11603doi: 10.18632/oncotarget.24294.
Vena, F., Jia, R., Esfandiari, A., Garcia-Gomez, J. J., Rodriguez-Justo, M., Ma, J., Syed, S., Crowley, L., Elenbaas, B., Goodstal, S., Hartley, J. A., & Hochhauser, D. (2018). MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models. Oncotarget, 9(14), 11592-11603. https://doi.org/10.18632/oncotarget.24294
Vena, Francesca, et al. "MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models." Oncotarget vol. 9,14 (2018): 11592-11603. doi: https://doi.org/10.18632/oncotarget.24294
Vena F, Jia R, Esfandiari A, Garcia-Gomez JJ, Rodriguez-Justo M, Ma J, Syed S, Crowley L, Elenbaas B, Goodstal S, Hartley JA, Hochhauser D. MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models. Oncotarget. 2018 Jan 22;9(14):11592-11603. doi: 10.18632/oncotarget.24294. eCollection 2018 Feb 20. PMID: 29545922; PMCID: PMC5837749.
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Oncotarget. 2018 Jan 22;9(14):11592-11603. doi: 10.18632/oncotarget.24294. eCollection 2018 Feb 20.

MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models.

Oncotarget

Francesca Vena, Ruochen Jia, Arman Esfandiari, Juan J Garcia-Gomez, Manuel Rodriguez-Justo, Jianguo Ma, Sakeena Syed, Lindsey Crowley, Brian Elenbaas, Samantha Goodstal, John A Hartley, Daniel Hochhauser

Affiliations

  1. Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6DD, UK.
  2. Department of Research Pathology, UCL Cancer Institute, London EC1M6BQ, UK.
  3. EMD Serono Research and Development Institute, Billerica 01821, MA, USA.

PMID: 29545922 PMCID: PMC5837749 DOI: 10.18632/oncotarget.24294

Abstract

Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines. Apoptosis was assessed by Caspase 3/7 assay and protein expression was detected by immunoblotting. DNA damage response was monitored with γH2AX and RAD51 immunofluorescence staining.

Keywords: DNA damage; MEK inhibitors; ovarian cancer; pancreatic cancer; targeted therapy

Conflict of interest statement

CONFLICTS OF INTEREST This research was funded by an educational grant from EMD Serono Research and Development Institute.

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