RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals myc as a driver of Pten-mutant metastasis.

TitleRapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals myc as a driver of Pten-mutant metastasis.
Publication TypeJournal Article
Year of Publication2014
AuthorsCho H, Herzka T, Zheng W, Qi J, Wilkinson JE, Bradner JE, Robinson BD, Castillo-Martin M, Cordon-Cardo C, Trotman LC
JournalCancer Discov
Volume4
Issue3
Pagination318-33
Date Published2014 Mar
ISSN2159-8290
KeywordsAnimals, 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.

DOI10.1158/2159-8290.CD-13-0346
Alternate JournalCancer Discov
PubMed ID24444712
Grant ListCA137050 / CA / NCI NIH HHS / United States
U01CA168409 / CA / NCI NIH HHS / United States
Related Faculty: 
Brian Robinson, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700