Title | RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals myc as a driver of Pten-mutant metastasis. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Cho H, Herzka T, Zheng W, Qi J, Wilkinson JE, Bradner JE, Robinson BD, Castillo-Martin M, Cordon-Cardo C, Trotman LC |
Journal | Cancer Discov |
Volume | 4 |
Issue | 3 |
Pagination | 318-33 |
Date Published | 2014 Mar |
ISSN | 2159-8290 |
Keywords | Animals, Azepines, Gene Expression Regulation, Neoplastic, Genetic Vectors, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neoplasm Metastasis, Neoplasms, Experimental, Prostatic Neoplasms, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-myc, PTEN Phosphohydrolase, Retroviridae, Triazoles, Tumor Suppressor Protein p53 |
Abstract | Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we find that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a "MYC-switch" away from AKT forms a critical and druggable event in PTEN-mutant prostate cancer metastasis and castration resistance. |
DOI | 10.1158/2159-8290.CD-13-0346 |
Alternate Journal | Cancer Discov |
PubMed ID | 24444712 |
Grant List | CA137050 / CA / NCI NIH HHS / United States U01CA168409 / CA / NCI NIH HHS / United States |
Related Faculty:
Brian Robinson, M.D.