MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

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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