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Molecular Cancer Research
Molecular Cancer Research

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Research Article

Loss of MAP3K7 sensitizes prostate cancer cells to CDK1/2 inhibition and DNA damage by disrupting homologous recombination

Satoshi Washino, Leah C. Rider, Lina Romero, Lauren K Jillson, Trisiani Affandi, Angela M Ohm, Elaine T Lam, Mary E. Reyland, James C Costello and Scott D Cramer
Satoshi Washino
Pharmacology, University of Colorado Anschutz Medical Campus
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Leah C. Rider
Pharmacology, University of Colorado Anschutz Medical Campus
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Lina Romero
Pharmocology, University of Colorado Anschutz Medical Campus
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Lauren K Jillson
Pharmacology, University of Colorado Anschutz Medical Center
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Trisiani Affandi
Craniofacial Biology, University of Colorado Anschutz Medical Center
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  • ORCID record for Trisiani Affandi
Angela M Ohm
Department of Craniofacial Biology, University of Colorado Denver
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Elaine T Lam
Internal Medicine/Medical Oncology, University of Colorado Anschutz Medical Campus
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Mary E. Reyland
Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus
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James C Costello
Pharmacology, University of Colorado Anschutz Medical Campus
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Scott D Cramer
Pharmacology, University of Colorado Anschutz Medical Campus
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  • For correspondence: scott.cramer@ucdenver.edu
DOI: 10.1158/1541-7786.MCR-18-1335
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Abstract

The combined loss of CHD1 and MAP3K7 promotes aggressive prostate cancer (CaP) by unknown mechanisms. Because these genes are both lost genetically in CaP, 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 CaP with co-loss of CHD1 & MAP3K7 with CaP diploid for these genes using TCGA 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 anti-proliferative 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 to 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. Co-treatment of dinaciclib with DNA damaging agents or PARP inhibitor resulted in a stronger cytotoxic effect on prostate cells with suppression of MAP3K7 compared to those without loss of MAP3K7, or to each single agent. Implications: These findings support that loss of MAP3K7 is a main contributing factor to drug response through disruption of homologous recombination in CaP.

  • Received December 17, 2018.
  • Revision received May 31, 2019.
  • Accepted July 8, 2019.
  • Copyright ©2019, American Association for Cancer Research.

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Published OnlineFirst July 12, 2019
doi: 10.1158/1541-7786.MCR-18-1335

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Loss of MAP3K7 sensitizes prostate cancer cells to CDK1/2 inhibition and DNA damage by disrupting homologous recombination
Satoshi Washino, Leah C. Rider, Lina Romero, Lauren K Jillson, Trisiani Affandi, Angela M Ohm, Elaine T Lam, Mary E. Reyland, James C Costello and Scott D Cramer
Mol Cancer Res July 12 2019 DOI: 10.1158/1541-7786.MCR-18-1335

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Loss of MAP3K7 sensitizes prostate cancer cells to CDK1/2 inhibition and DNA damage by disrupting homologous recombination
Satoshi Washino, Leah C. Rider, Lina Romero, Lauren K Jillson, Trisiani Affandi, Angela M Ohm, Elaine T Lam, Mary E. Reyland, James C Costello and Scott D Cramer
Mol Cancer Res July 12 2019 DOI: 10.1158/1541-7786.MCR-18-1335
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Molecular Cancer Research
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