Copy number alterations (CNAs) 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 state prostate cancer.
Written by:
Wanjala J, Taylor BS, Chapinski C, Hieronymus H, Wongvipat J, Chen Y, Nanjangud GJ, Schultz N, Xie Y, Liu S, Lu W, Yang Q, Sander C, Chen Z, Sawyers CL, Carver BS. Are you the author?
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; Computation Biology Center, Memorial Sloan-Kettering Cancer Center; Howard Hughes Medical Institute, New York, New York; Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center; Computational Biology, Memorial Sloan-Kettering Cancer Center; Biochem and Cancer Biology, Meharry Medical College; Cancer Biology, Meharry Medical College; Program in Human Oncology and Pathogenesis, Memorial Sloan Kettering Cancer Center; Human Oncology and Pathogenesis Program, Department of Surgery and Urology Service, Memorial Sloan-Kettering Cancer Center.
Reference: Mol Cancer Ther. 2014 Nov 7. pii: molcanther.0542.2014.
doi: 10.1158/1535-7163.MCT-14-0542-T
PubMed Abstract
PMID: 25381262