Profiling Prostate Cancer Therapeutic Resistance

Abstract

The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic castration resistant prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during tumor progression. A characteristic feature of EMT landscape is loss of E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting metastasis and chemoresistance. The targetable interactions between androgens/AR and TGF-β signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of biomarker discovery.

Keywords: androgen receptor; epithelial plasticity; metabolic changes; tumor landscape.

Figure 1

Signaling pathways contributing to therapeutic resistance in prostate cancer and their targetable interactions via EMT to MET interconversions. (A) First and second line antiandrogens (abiraterone and enzalutamide) target the AR signaling cascade by reducing testosterone production or inhibiting the binding site of AR and subsequent translocation to the nucleus, respectively. (B) Mutations in AR signaling promote transcriptional activation despite ADT. (C) TGF-β bi-functionally affects cell growth and differentiation through intracellular SMAD and non-SMAD signaling including MAP-kinases, loss of E-cadherin, and consequential changes in cell polarity. (D) Distinct cell types such as myofibroblasts, CAFs, neuroendocrine (NE) cells, and MDSCs (Myeloid-derived suppressor cells) within the microenvironment may navigate therapeutic resistance to antiandrogens and taxane chemotherapy by engaging ECM components, growth factors such as TGF-β, VEGF, IGF, mitotic promoters, and immune suppression. (E) Loss and gain of E-cadherin serves as a causative factor of cell polarity and biomarker of EMT, respectively, under the transcriptional repression of SNAI, ZEB1, and Twist-related protein (TWIST) (nuclear transcription factors). Color code: Orange/yellow: normal cellular signaling, red: promotors of therapeutic resistance, blue: existing or experimental therapies for prostate cancer.