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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Helge Gad1, Tobias Koolmeister1, Ann-Sofie Jemth1

  • 11] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].

Nature
|April 4, 2014
PubMed

Insights

Cancer cells depend on MTH1 protein to prevent DNA damage from oxidized nucleotides. Inhibiting MTH1 with novel compounds TH287 and TH588 causes cancer cell death, validating MTH1 as a promising anticancer target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Cancer cells exhibit redox dysregulation, producing reactive oxygen species that damage DNA and deoxynucleotide triphosphates (dNTPs).
  • The MTH1 protein plays a crucial role in sanitizing oxidized dNTP pools, preventing the incorporation of damaged bases during DNA replication.

Purpose of the Study:

  • To investigate the essentiality of MTH1 in cancer cells and its potential as an anticancer therapeutic target.
  • To identify and characterize novel small molecule inhibitors of MTH1.

Main Methods:

  • Utilized cell-based assays to assess MTH1 dependency in cancer cells.
  • Developed and characterized small molecules TH287 and TH588 as MTH1 inhibitors.
  • Determined co-crystal structures of MTH1 with inhibitors.
  • Evaluated in vivo efficacy in patient-derived mouse xenografts.

Main Results:

  • Cancer cells, unlike normal cells, are critically dependent on MTH1 activity to prevent DNA damage and cell death.
  • Small molecules TH287 and TH588 potently and selectively inhibit MTH1 in cells.
  • Inhibitor-bound structures confirmed binding within the MTH1 active site.
  • Treatment with TH287/TH588 led to oxidized dNTP incorporation, DNA damage, cytotoxicity, and therapeutic responses in vivo.

Conclusions:

  • MTH1 is a cancer-specific vulnerability, essential for cancer cell survival.
  • MTH1 inhibitors TH287 and TH588 represent a novel class of anticancer agents.
  • This study validates the non-oncogene addiction concept and MTH1 as a cancer-phenotypic lethal target.

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