Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling

Jackie Wanjala, Barry S. Taylor, Caren Chapinski, Haley Hieronymus, John Wongvipat, Yu Chen, Gouri J. Nanjangud, Nikolaus Schultz, Yingqiu Xie, Shenji Liu, Wenfu Lu, Qing Yang, Chris Sander, Zhenbang Chen, Charles L. Sawyers, Brett S. Carver

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Copy-number alterations (CNA) are among the most common molecular events in human prostate cancer genomes and are associated with worse prognosis. Identification of the oncogenic drivers within these CNAs is challenging due to the broad nature of these genomic gains or losses which can include large numbers of genes within a given region. Here, we profiled the genomes of four genetically engineered mouse prostate cancer models that reflect oncogenic events common in human prostate tumors, with the goal of integrating these data with human prostate cancer datasets to identify shared molecular events. Met was amplified in 67% of prostate tumors from Pten p53 prostate conditional null mice and in approximately 30% of metastatic human prostate cancer specimens, often in association with loss of PTEN and TP53. In murine tumors with Met amplification, Met copy-number gain and expression was present in some cells but not others, revealing intratumoral heterogeneity. Forced MET overexpression in non-MET-amplified prostate tumor cells activated PI3K and MAPK signaling and promoted cell proliferation and tumor growth, whereas MET kinase inhibition selectively impaired the growth of tumors with Met amplification. However, the impact of MET inhibitor therapy was compromised by the persistent growth of non-Met-amplified cells within Met-amplified tumors. These findings establish the importance of MET in prostate cancer progression but reveal potential limitations in the clinical use of MET inhibitors in late-stage prostate cancer.

Original languageEnglish
Pages (from-to)278-288
Number of pages11
JournalMolecular Cancer Therapeutics
Volume14
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling'. Together they form a unique fingerprint.

  • Cite this

    Wanjala, J., Taylor, B. S., Chapinski, C., Hieronymus, H., Wongvipat, J., Chen, Y., Nanjangud, G. J., Schultz, N., Xie, Y., Liu, S., Lu, W., Yang, Q., Sander, C., Chen, Z., Sawyers, C. L., & Carver, B. S. (2015). Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling. Molecular Cancer Therapeutics, 14(1), 278-288. https://doi.org/10.1158/1535-7163.MCT-14-0542-T