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Mol Cancer Res. 2019 Oct;17(10):1985-1998. doi: 10.1158/1541-7786.MCR-18-1335. Epub 2019 Jul 12.

Loss of MAP3K7 Sensitizes Prostate Cancer Cells to CDK1/2 Inhibition and DNA Damage by Disrupting Homologous Recombination.

Author information

1
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
2
Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
3
Department of Internal Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
4
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Scott.cramer@ucdenver.edu.
#
Contributed equally

Abstract

The combined loss of CHD1 and MAP3K7 promotes aggressive prostate cancer by unknown mechanisms. Because both of these genes are lost genetically in prostate cancer, they cannot be directly targeted. We applied an established computational systems pharmacology approach (TRAP) to identify altered signaling pathways and associated druggable targets. We compared gene expression profiles of prostate cancer with coloss of CHD1 and MAP3K7 with prostate cancer diploid for these genes using The Cancer Genome Atlas patient samples. This analysis prioritized druggable target genes that included CDK1 and CDK2. We validated that inhibitors of these druggable target genes, including the CDK1/CDK2 inhibitor dinaciclib, had antiproliferative and cytotoxic effects selectively on mouse prostate cells with knockdown of Chd1 and Map3k7. Dinaciclib had stronger effects on prostate cells with suppression of Map3k7 independent of Chd1 and also compared with cells without loss of Map3k7. Dinaciclib treatment reduced expression of homologous recombination (HR) repair genes such as ATM, ATR, BRCA2, and RAD51, blocked BRCA1 phosphorylation, reduced RAD51 foci formation, and increased γH2AX foci selectively in prostate cells with suppression of Map3k7, thus inhibiting HR repair of chromosomal double-strand breaks. Dinaciclib-induced HR disruption was also observed in human prostate cells with knockdown of MAP3K7. Cotreatment of dinaciclib with DNA-damaging agents or PARP inhibitor resulted in a stronger cytotoxic effect on prostate cells with suppression of MAP3K7 compared with those without loss of MAP3K7, or to each single agent. IMPLICATIONS: These findings demonstrate that loss of MAP3K7 is a main contributing factor to drug response through disruption of HR in prostate cancer.

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