Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition

Mol Cancer Ther. 2021 Jan;20(1):64-75. doi: 10.1158/1535-7163.MCT-20-0259. Epub 2020 Oct 21.


Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but often lethal cancer that is diagnosed at a median age of 24 years. Optimal management of patients is not well defined, and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of cancer provided insights facilitating diagnostic and therapeutic measures against this disease. We show here that the BET inhibitor OTX015 acts in synergy with the MEK inhibitor cobimetinib to repress the proliferation of SCCOHT in vivo Notably, this synergy is also observed in some SMARCA4-expressing ovarian adenocarcinoma models intrinsically resistant to BETi. Mass spectrometry, coupled with knockdown of newly found targets such as thymidylate synthase, revealed that the repression of a panel of proteins involved in nucleotide synthesis underlies this synergy both in vitro and in vivo, resulting in reduced pools of nucleotide metabolites and subsequent cell-cycle arrest. Overall, our data indicate that dual treatment with BETi and MEKi represents a rational combination therapy against SCCOHT and potentially additional ovarian cancer subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azetidines / pharmacology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • Drug Synergism
  • Epigenesis, Genetic* / drug effects
  • Female
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Proteins / metabolism
  • Nucleotides / metabolism*
  • Ovarian Neoplasms / drug therapy
  • Piperidines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • S Phase / drug effects
  • Xenograft Model Antitumor Assays


  • Azetidines
  • Neoplasm Proteins
  • Nucleotides
  • Piperidines
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • cobimetinib