Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells

Cancer Lett. 2014 Jun 1;347(2):212-24. doi: 10.1016/j.canlet.2014.02.016. Epub 2014 Feb 24.

Abstract

Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.

Keywords: Drug resistance; FOXO1; MEK inhibitors; Ovarian carcinoma; Platinum compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cell Line, Tumor
  • Enzyme Activation
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Humans
  • In Situ Nick-End Labeling
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Organoplatinum Compounds / administration & dosage
  • Organoplatinum Compounds / pharmacology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*

Substances

  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Organoplatinum Compounds
  • MAP Kinase Kinase Kinases