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:
- Name: BJ
Description: Human Fibroblasts - Name: Cco-7
- Name: DU 145
Description: Human prostate carcinoma cells - Name: Glioma A
- Name: HCC1937
Description: Human ductal breast carcinoma cell line.
Known as: HCC-1937. - Name: HCC38
Description: Human primary ductal carcinoma (TNM stage IIB, grade 3) from mammary gland
Known as: ATCC CRL-2314 - Name: HEC-59
Description: Human endometrial adenocarcinoma
Known as: HEC59 ; Hec59 - Name: HEK-293T
Description: Human embryonic kidney Fibroblast
Known as: HEK293T, 293T - Name: HeLa
Description: Human cervix epitheloid carcinoma cells - Name: Hep G2
Description: Human hepatocarcinoma cells - Name: LNCaP
Description: Human prostate carcinoma cells - Name: MDA-MB-231
Description: Human breast adenocarcinoma cells
Known as: MDAMB231 - Name: MRC-9
Description: Human lung fibroblast
Known as: ATCC CCL-212 - Name: PC-3
Description: Human prostate carcinoma cells
Known as: PC3, PC 3 - Name: SW480
Description: Human colon adenocarcinoma cells - Name: SW620
Description: Human colon adenocarcinoma cells - Name: T-47D
Description: Human breast ductal carcinoma cells
Known as: T 47 - Name: U-2 OS
Description: Human bone osteosarcoma
Known as: U2OS - Name: VACO 4A
Description: Human rectal adenocarcinoma
Known as: VACO4A ; Vaco4A - Name: VH10
Description: Human
Known as: VH-10
- Name: BJ
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.