Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation

Cancer Cell. 2015 Nov 9;28(5):557-568. doi: 10.1016/j.ccell.2015.09.015.

Abstract

Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a synthetic lethal interaction in which H3K36me3-deficient cancers are acutely sensitive to WEE1 inhibition. We show that RRM2, a ribonucleotide reductase subunit, is the target of this synthetic lethal interaction. RRM2 is regulated by two pathways here: first, H3K36me3 facilitates RRM2 expression through transcription initiation factor recruitment; second, WEE1 inhibition degrades RRM2 through untimely CDK activation. Therefore, WEE1 inhibition in H3K36me3-deficient cells results in RRM2 reduction, critical dNTP depletion, S-phase arrest, and apoptosis. Accordingly, this synthetic lethality is suppressed by increasing RRM2 expression or inhibiting RRM2 degradation. Finally, we demonstrate that WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumor xenografts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blotting, Western
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Lysine / genetics
  • Lysine / metabolism
  • Methylation / drug effects
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Sequence Data
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / prevention & control
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nucleotides / genetics
  • Nucleotides / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Pyrimidinones
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonucleoside Diphosphate Reductase / genetics
  • Ribonucleoside Diphosphate Reductase / metabolism
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • Histones
  • Nuclear Proteins
  • Nucleotides
  • Pyrazoles
  • Pyrimidines
  • Pyrimidinones
  • ribonucleotide reductase M2
  • Ribonucleoside Diphosphate Reductase
  • Histone-Lysine N-Methyltransferase
  • Set2 protein, human
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • adavosertib
  • Lysine