Both the PI3K → Akt → mTOR and mitogen-activated protein kinase (MAPK) signaling pathways are often deregulated in prostate tumors with poor prognosis.
Here we describe a new genetically engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and extracellular signal-regulated kinase 1/2 (ERK1/2) MAPK signaling is activated by inducible expression of a BRAF(V600E) oncogene. These tissue-specific compound mutant mice develop lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow, and lungs where they form overt metastases in approximately 30% of the cases. Activation of PI3K → Akt → mTOR and MAPK signaling pathways in these prostate tumors cooperate to upregulate c-Myc. Accordingly, therapeutic treatments with rapamycin and PD0325901 to target these pathways, respectively, attenuate c-Myc levels and reduce tumor and metastatic burden. Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K → Akt → mTOR and ERK1/2 MAPK signaling pathways.
Written by:
Wang J, Kobayashi T, Floc'h N, Kinkade CW, Aytes A, Dankort D, Lefebvre C, Mitrofanova A, Cardiff RD, McMahon M, Califano A, Shen MM, Abate-Shen C. Are you the author?
Departments of Urology and Pathology and Cell Biology, Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Departments of Medicine and Genetics & Development, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; and Center for Comparative Medicine and Department of Pathology, School of Medicine, University of California, Davis, California.
Reference: Cancer Res. 2012 Sep 15;72(18):4765-4776.
doi: 10.1158/0008-5472.CAN-12-0820
PubMed Abstract
PMID: 22836754
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