Description:
Abstract One major prerequisite to develop targeted therapies is the identification of relevant cellular targets and the identification of the relevant patient population in which to test these therapies. Although androgen ablation therapy, surgery and radiation therapy are effective for the treatment of local prostate cancer (PCa), there is no effective treatment available for patients with metastatic disease. The receptor tyrosine kinase Axl has been implicated in the pathology of many cancers. Increased Axl expression correlates with metastasis, aggressive behavior, and poor survival and have been linked with resistance to chemotherapeutic regimens in tumors. Interestingly, in these reports inhibition of Axl leads to restoration of sensitivity to drug therapy, indicating that Axl may represent a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to some drugs. We have shown that Axl is overexpressed in PCa and is an essential regulator of PCa proliferation and tumor growth. Axl expression is elevated in hormone-refractory PCa cell lines and Axl knockdown reduces migration and invasion and tumor formation in vivo. The Axl ligand, GAS6, acts as a growth and/or survival factor and its binding to Axl activates PI3K and its downstream targets S6K and Akt. Activation of these pathways has been reported to induce nuclear translocation of the transcription factor nuclear factor kappa B (NF-κB), IL-6 production and STAT3 activation. The molecule named R428 (now renamed BGB324) inhibits in a dose-dependent manner Gas6 stimulated Axl autophosphorylation and activity with high specificity, selectivity, and affinity and blocks Axl-dependent signaling events, such as Akt phosphorylation, cell invasion, and pro-inflammatory cytokine production. R428/BGB324 effectively prevents or reverses acquired resistance to several cancer therapies in preclinical models. Most importantly, as a result of these and other encouraging preclinical findings of therapeutic value this first-in-class, highly selective Axl inhibitor has entered the clinical trial phase. Docetaxel, the main chemotherapeutic drug used in aggressive prostate cancer treatment, has shown limited efficacy against metastatic PCa, primarily due to invariable development of drug resistance, necessitating a thorough investigation of the mechanisms underlying this drug resistance and the development of novel, more efficacious therapies to prevent or overcome resistance. Preliminary data from our laboratory provide strong evidence for the notion that Axl plays a pivotal role in resistance to docetaxel and possibly cabazitaxel treatment. Importantly, Axl inhibitor R428 enhances docetaxel efficacy. Citation Format: Luiz F. Zerbini. Emerging signaling pathways in prostate cancer therapy [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA22.