Citation

  • Authors: Gad, H., Koolmeister, T., Jemth, A. S., Eshtad, S., Jacques, S. A., Strom, C. E., Svensson, L. M., Schultz, N., Lundback, T., Einarsdottir, B. O., Saleh, A., Gokturk, C., Baranczewski, P., Svensson, R., Berntsson, R. P., Gustafsson, R., Stromberg, K., Sanjiv, K., Jacques-Cordonnier, M. C., Desroses, M., Gustavsson, A. L., Olofsson, R., Johansson, F., Homan, E. J., Loseva, O., Brautigam, L., Johansson, L., Hoglund, A., Hagenkort, A., Pham, T., Altun, M., Gaugaz, F. Z., Vikingsson, S., Evers, B., Henriksson, M., Vallin, K. S., Wallner, O. A., Hammarstrom, L. G., Wiita, E., Almlof, I., Kalderen, C., Axelsson, H., Djureinovic, T., Puigvert, J. C., Haggblad, M., Jeppsson, F., Martens, U., Lundin, C., Lundgren, B., Granelli, I., Jensen, A. J., Artursson, P., Nilsson, J. A., Stenmark, P., Scobie, M., Berglund, U. W., Helleday, T.
  • Year: 2014
  • Journal: Nature 508 215-21
  • Applications: in vitro / DNA, siRNA / INTERFERin, jetPEI
  • Cell types:
    1. Name: BJ
      Description: Human Fibroblasts
    2. Name: Cco-7
    3. Name: DU 145
      Description: Human prostate carcinoma cells
    4. Name: Glioma A
    5. Name: HCC1937
      Description: Human ductal breast carcinoma cell line.
      Known as: HCC-1937.
    6. Name: HCC38
      Description: Human primary ductal carcinoma (TNM stage IIB, grade 3) from mammary gland
      Known as: ATCC CRL-2314
    7. Name: HEC-59
      Description: Human endometrial adenocarcinoma
      Known as: HEC59 ; Hec59
    8. Name: HEK-293T
      Description: Human embryonic kidney Fibroblast
      Known as: HEK293T, 293T
    9. Name: HeLa
      Description: Human cervix epitheloid carcinoma cells
    10. Name: Hep G2
      Description: Human hepatocarcinoma cells
    11. Name: LNCaP
      Description: Human prostate carcinoma cells
    12. Name: MDA-MB-231
      Description: Human breast adenocarcinoma cells
      Known as: MDAMB231
    13. Name: MRC-9
      Description: Human lung fibroblast
      Known as: ATCC CCL-212
    14. Name: PC-3
      Description: Human prostate carcinoma cells
      Known as: PC3, PC 3
    15. Name: SW480
      Description: Human colon adenocarcinoma cells
    16. Name: SW620
      Description: Human colon adenocarcinoma cells
    17. Name: T-47D
      Description: Human breast ductal carcinoma cells
      Known as: T 47
    18. Name: U-2 OS
      Description: Human bone osteosarcoma
      Known as: U2OS
    19. Name: VACO 4A
      Description: Human rectal adenocarcinoma
      Known as: VACO4A ; Vaco4A
    20. Name: VH10
      Description: Human
      Known as: VH-10

Method

10 nM siRNA

Abstract

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

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