Cho, H., Herzka, T., Zheng, W., Qi, J., Wilkinson, J. E., Bradner, J. E., Robinson, B. D., Castillo-Martin, M., Cordon-Cardo, C., Trotman, L. C. (January 2014) RapidCaP, a novel GEM model for analysis and therapy of metastatic prostate cancer, reveals Myc as a driver of Pten-mutant metastasis. Cancer Discovery, 4 (3). pp. 318-33. ISSN 21598274
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 prostate. We show that in Pten-deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by 4 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 show 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.
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