Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination

Nat Commun. 2018 Sep 24;9(1):3872. doi: 10.1038/s41467-018-06287-x.


The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biphenyl Compounds / pharmacology*
  • Biphenyl Compounds / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Chemoradiotherapy / methods
  • DNA Breaks, Double-Stranded / radiation effects
  • Dideoxynucleotides / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Hydroxybenzoates / pharmacology*
  • Hydroxybenzoates / therapeutic use
  • Neoplasms / therapy*
  • Phosphofructokinase-2 / antagonists & inhibitors*
  • Phosphofructokinase-2 / genetics
  • Phosphofructokinase-2 / metabolism
  • RNA, Small Interfering / metabolism
  • Radiation Tolerance / drug effects
  • Radiation Tolerance / genetics
  • Radiation, Ionizing
  • Recombinational DNA Repair / drug effects
  • Recombinational DNA Repair / radiation effects
  • Sulfones / pharmacology*
  • Sulfones / therapeutic use


  • Antineoplastic Agents
  • Biphenyl Compounds
  • Dideoxynucleotides
  • Enzyme Inhibitors
  • Hydroxybenzoates
  • RNA, Small Interfering
  • Sulfones
  • PFKFB3 protein, human
  • Phosphofructokinase-2