Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling.
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.
Human Oncology and Pathogenesis Oncology Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
Jackie
J
Wanjala
Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York.
Barry S
BS
Taylor
Human Oncology and Pathogenesis Oncology Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
Caren
C
Chapinski
Human Oncology and Pathogenesis Oncology Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
Haley
H
Hieronymus
Human Oncology and Pathogenesis Oncology Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
John
J
Wongvipat
Human Oncology and Pathogenesis Oncology Program, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
Yu
Y
Chen
Molecular Cytogenetics Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York.
Gouri J
GJ
Nanjangud
Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York.
Nikolaus
N
Schultz
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee.
Yingqiu
Y
Xie
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee.
Shenji
S
Liu
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee.
Wenfu
W
Lu
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee.
Qing
Q
Yang
Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York.
Chris
C
Sander
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee.
Zhenbang
Z
Chen
Human Oncology and Pathogenesis Oncology Program, Memorial Sloan-Kettering Cancer Center, New York, New York. Howard Hughes Medical Institute, Chevy Chase, Maryland.
Charles L
CL
Sawyers
Human Oncology and Pathogenesis Oncology Program, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Surgery and Division of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York. carverb@mskcc.org.
Brett S
BS
Carver
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D016678:Genome; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse