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

The combined loss of <i>CHD1</i> and <i>MAP3K7</i> 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 <i>CHD1</i> and <i>MAP3K7</i> with prostate cancer diploid for these genes using The Cancer Genome Atlas patient samples. This analysis prioritized druggable target genes that included <i>CDK1</i> and <i>CDK2</i>. We validated that inhibitors of these druggable target genes, including the <i>CDK1</i>/<i>CDK2</i> inhibitor dinaciclib, had antiproliferative and cytotoxic effects selectively on mouse prostate cells with knockdown of <i>Chd1</i> and <i>Map3k7</i>. Dinaciclib had stronger effects on prostate cells with suppression of <i>Map3k7</i> independent of <i>Chd1</i> and also compared with cells without loss of <i>Map3k7</i>. Dinaciclib treatment reduced expression of homologous recombination (HR) repair genes such as <i>ATM, ATR, BRCA2</i>, and <i>RAD51</i>, blocked BRCA1 phosphorylation, reduced RAD51 foci formation, and increased γH2AX foci selectively in prostate cells with suppression of <i>Map3k7</i>, thus inhibiting HR repair of chromosomal double-strand breaks. Dinaciclib-induced HR disruption was also observed in human prostate cells with knockdown of <i>MAP3K7</i>. Cotreatment of dinaciclib with DNA-damaging agents or PARP inhibitor resulted in a stronger cytotoxic effect on prostate cells with suppression of <i>MAP3K7</i> compared with those without loss of <i>MAP3K7</i>, or to each single agent. IMPLICATIONS: These findings demonstrate that loss of <i>MAP3K7</i> is a main contributing factor to drug response through disruption of HR in prostate cancer.