Abstract IA4: Reciprocal feed-back regulation of the PI3K and AR pathways in prostate cancer: A mechanism of innate resistance

Prostate cancer is the most commonly diagnosed malignancy in men and the second most common cause of male cancer deaths. Despite effective primary therapy, a significant percentage of patients will develop recurrent and progressive disease. Androgen deprivation therapy remains the primary modality for the treatment of advanced and metastatic prostate cancer; however, the median time to progression to castrate resistant disease is approximately 18 months. While there have been great strides made in the treatment of castrate resistant prostate cancer with the recent approval of several chemotherapy regimens and the novel androgen biosynthesis inhibitor abiaterone, the median improvement in survival has only been measured in months. Thus there is still a significant need for the development of novel therapies targeting critical biologic pathways in prostate cancer, with the ultimate goal of achieving a complete clinical response. Through the comprehensive molecular profiling of prostate cancer we have identified a number of oncogenic pathways frequently altered in prostate cancer, such as the PI3K pathway, that are attractive targets for therapy (1). Targeted therapy has emerged as the gold standard of individualized patient therapy for a number of malignancies; however, with rare exception, the majority of these treatments fail to produce long-term durable response or complete remissions. In particular, the mTORC1 inhibitor RAD001 is only marginally effective in most tumor types in which PI3K signaling is expected to be dysregulated and in particular, has no activity in prostate cancer. Chandarlapaty and colleagues discovered an important factor that may account for the modest activity of PI3K pathway inhibitors. Physiologic signaling is regulated and turned off by feedback inhibition of the pathway. Constitutive activation of signaling by oncoproteins is accompanied by marked feedback inhibition throughout the network, especially of receptor function (2). Thus, feedback inhibition of upstream and parallel signaling pathways by the oncoprotein is, in part, responsible for the oncogene dependence of tumors and their sensitivity to inhibitors. However, inhibition of oncogenic targets is accompanied by relief of this negative feedback, which induces hyperactivation of receptor signaling. For instance, activation of PI3K signaling decreases HER3, and insulin receptor and IGF1R levels and phosphorylation, whereas inhibition of AKT relieves this feedback, resulting upregulation and hyper-activation of these receptor tyrosine kinases. Previous studies have demonstrated that HER2/3 plays a critical role in regulating AR stability and activity (3). Through our work, we found that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases (4). Furthermore, we discovered that inhibition of AR leads to the activation of a number of kinases including AKT by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. Identifying this reciprocal feedback regulation provides rationale for the evaluation of combination therapy targeting the PI3K and AR pathways. These findings have important clinical implications in patients with prostate cancer and understanding the feedback associated with inhibition of these pathways is important for development of clinical trials.