Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling Journal Article
| Authors: | 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. |
| Article Title: | Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling |
| 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. |
| Keywords: | immunohistochemistry; mitogen activated protein kinase; protein kinase b; cancer growth; nonhuman; cell proliferation; mouse; phosphatidylinositol 3 kinase; protein p53; protein tyrosine kinase inhibitor; prostate cancer; fluorescence in situ hybridization; myc protein; western blotting; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; genomics; comparative genomic hybridization; scatter factor receptor; human; male; priority journal; article; genetically engineered mouse strain |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 14 |
| Issue: | 1 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2015-01-01 |
| Start Page: | 278 |
| End Page: | 288 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-14-0542-t |
| PROVIDER: | scopus |
| PMCID: | PMC4297258 |
| PUBMED: | 25381262 |
| DOI/URL: | |
| Notes: | Export Date: 2 March 2015 -- Source: Scopus |
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