Abstract B45: Combinatorial activation of PI3-kinase and Ras-Raf signaling in mouse models of advanced prostate cancer

Abstract

Abstract Concomitant activation of the PI3K and MAP kinase pathways is a hallmark of aggressive prostate cancer. Here, we describe a series of new genetically engineered mouse models of prostate cancer in which PI3K-Akt-mTOR signaling is activated through inducible deletion of PTEN, while MAP kinase signaling is activated through inducible expression of oncogenic mutants of either BRAF or KRAS oncogenes [BRAFV600E (NPB mice) and KRASG12D (NPK mice), respectively]. Activation of PI3K-Akt-mTOR and MAPK signaling pathways in NPB mice results in the formation of 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. Molecularly, tumors in the NPB mice cooperate to up-regulate c-MYC oncogene and accordingly, therapeutic treatments with an mTOR inhibitor (rapamycin) and the MEK1/2 inhibitor (PD0325901) results in attenuation of c-MYC levels and reduction primary tumor and metastatic burden. These 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. On the other hand, activation of PI3K-Akt-mTOR and MAP kinase signaling pathways in the NPK mice, results in prostate tumors that are also inherently castration resistant and metastasize to distant organs with 100% penetrance. Our studies show that in the NPK mice, dissemination is an early event in tumorigenesis although overt metastatic growth only occurs in late stage tumors coinciding with the upregulation of the ETS family member ETV4 in the primary tumor. Functional studies have shown that silencing of Etv4 in a metastatic cell line derived from this mouse model (NPK mice) abrogates the metastatic phenotype but does not affect tumor growth. These findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer. Taken together, our analysis of the molecular mechanisms involved in the distinct metastatic potential of these two new mouse models provides us with clinically relevant tools to conduct preclinical studies. Citation Format: Jingqiang Wang, Alvaro Aytes, Cory Abate-Shen. Combinatorial activation of PI3-kinase and Ras-Raf signaling in mouse models of advanced prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B45.