Co-Targeting ErbB Receptors and the PI3K/AKT Axis in Androgen-Independent Taxane-Sensitive and Taxane-Resistant Human Prostate Cancer Cells

SIMPLE SUMMARY: Advanced prostate cancer that has progressed after standard therapies such as hormone therapy and taxane-based chemotherapies is an invariably lethal disease state with limited treatment options. There remains an important need to continue to identify new treatment approaches for such patients. We used two cell culture models of prostate cancer that are resistant to hormonal therapy and chemotherapy, and which also manifest some characteristics that are often associated with advanced prostate cancer, such as neuroendocrine differentiation, to evaluate the potential anti-cancer effects of targeting the key molecules, ErbB receptors and AKT. Using several complementary approaches, we found that the concurrent targeting of ErbB receptors and AKT with specific inhibitors was more effective than targeting each of them individually, independent of the underlying molecular characteristics or relative degrees of resistance to the taxanes that defined the prostate cancer models that were studied. Enhanced anti-tumor responses occurred both in vitro and in vivo with dual targeting, with the consistent inhibition particularly of AKT occurring in both settings. These studies provide a framework to evaluate the role of signal pathway modulation as a potential therapeutic strategy in treatment-refractory prostate cancer. ABSTRACT: Using two representative models of androgen-independent prostate cancer (PCa), PC3 and DU145, and their respective paclitaxel- and docetaxel-resistant derivatives, we explored the anti-tumor activity of targeting the ErbB receptors and AKT using small-molecule kinase inhibitors. These cells manifest varying degrees of neuroendocrine differentiation characteristics and differ in their expression of functional PTEN. Although the specific downstream signaling events post the ErbB receptor and AKT co-targeting varied between the PC3- and DU145-lineage cells, synergistic anti-proliferative and enhanced pro-apoptotic responses occurred across the wild-type and the taxane-resistant cells, independent of their basal AKT activation state, their degree of paclitaxel- or docetaxel-resistance, or whether this resistance was mediated by the ATP Binding Cassette transport proteins. Dual targeting also led to enhanced anti-tumor responses in vivo, although there was pharmacodynamic discordance between the PCa cells in culture versus the tumor xenografts in terms of the relative activation and inhibition states of AKT and ERK under basal conditions and upon AKT and/or ErbB targeting. The consistent inhibition, particularly of AKT, occurred both in vitro and in vivo, independent of the underlying PTEN status. Thus, co-targeting AKT with ErbB, and possibly other partners, may be a useful strategy to explore further for potential therapeutic effect in advanced PCa.