RT Journal Article
SR Electronic
T1 Identifying Actionable Targets through Integrative Analyses of GEM Model and Human Prostate Cancer Genomic Profiling
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 278
OP 288
DO 10.1158/1535-7163.MCT-14-0542-T
VO 14
IS 1
A1 Wanjala, Jackie
A1 Taylor, Barry S.
A1 Chapinski, Caren
A1 Hieronymus, Haley
A1 Wongvipat, John
A1 Chen, Yu
A1 Nanjangud, Gouri J.
A1 Schultz, Nikolaus
A1 Xie, Yingqiu
A1 Liu, Shenji
A1 Lu, Wenfu
A1 Yang, Qing
A1 Sander, Chris
A1 Chen, Zhenbang
A1 Sawyers, Charles L.
A1 Carver, Brett S.
YR 2015
UL http://mct.aacrjournals.org/content/14/1/278.abstract
AB 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. Mol Cancer Ther; 14(1); 278–88. ©2014 AACR.