Docetaxel-based chemotherapy is established as a first-line treatment and standard of care for patients with metastatic castration-resistant prostate cancer. However, half of the patients do not respond to treatment and those do respond eventually become refractory. A better understanding of the resistance mechanisms to taxane chemotherapy is both urgent and clinical significant, as taxanes (docetaxel and cabazitaxel) are being used in various clinical settings. Sustained signaling through the androgen receptor (AR) has been established as a hallmark of CRPC. Recently, splicing variants of AR (AR-Vs) that lack the ligand-binding domain (LBD) have been identified. These variants are constitutively active and drive prostate cancer growth in a castration-resistant manner. In taxane-resistant cell lines, we found the expression of a major variant, AR-V7, was upregulated. Furthermore, ectopic expression of two clinically relevant AR-Vs (AR-V7 and ARV567es), but not the full-length AR (AR-FL), reduced the sensitivities to taxanes in LNCaP cells. Treatment with taxanes inhibited the transcriptional activity of AR-FL, but not those of AR-Vs. This could be explained, at least in part, due to the inability of taxanes to block the nuclear translocation of AR-Vs. Through a series of deletion constructs, the microtubule-binding activity was mapped to the LBD of AR. Finally, taxane-induced cytoplasm sequestration of AR-FL was alleviated when AR-Vs were present. These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy.
Purpose The majority of prostate cancer mortality can be attributed to metastatic castration-resistant prostate cancer, an advanced stage which remains incurable despite recent advances. The androgen receptor (AR) signaling axis remains active in CRPC. Recent studies suggest that the expression of an AR splice variant, AR-V7, may underlie resistance to abiraterone and enzalutamide. However, controversy exists over the optimal assay. The objective of this study is to develop a fast and sensitive assay for AR splice variants (AR-Vs) in patients. Materials and Methods Two approaches were assessed in this study. The first was based on depletion of leukocytes and the second used RNA purified directly from whole blood preserved in PAXgene tubes. Transcript expression was analyzed by quantitative RT-PCR. Results Through side-by-side comparison, we concluded that the whole-blood approach was suitable for the detection of AR-Vs. The specificity of the assay was corroborated in a cancer-free cohort. Using the PAXgene assay, samples from a cohort of 46 CRPC patients were analyzed. Overall, AR-V7 and ARv567es were detected in 67.53% and 29.87% of the samples, respectively. Statistical analysis revealed a strong association of AR-V positivity with a history of second-line hormonal therapies. Conclusions To our knowledge, this study is the first to demonstrate PAXgene-preserved whole blood can be used to obtain clinically relevant information regarding the expression of two AR-Vs. The data from a CRPC cohort support a role of AR-Vs in resistance to therapies targeting the AR ligand-binding domain.
The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intra-tumor transformation process is poorly understood.We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single cell transcriptomes and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stressresponsive DTC cells, inflammatory ATC cells (iATCs), mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Further, our analysis identified two important milestones: 1) a diploid stage, where iATC cells were diploids with inflammatory phenotypes, and 2) an aneuploid stage, where mATCs gained aneuploid genomes and mesenchymal phenotypes producing excessive collagens and collagen-interacting receptors. In parallel, cancer-associatedfibroblasts showed strong interactions among mesenchymal cell-types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for ATC.
The androgen receptor (AR) is a ligand-activated nuclear receptor that plays a critical role in normal prostate physiology, as well as in the development and progression of prostate cancer. In addition to the classical paradigm in which AR exerts its biological effects in the nucleus by orchestrating the expression of the androgen-regulated transcriptome, there is considerable evidence supporting a rapid, nongenomic activity mediated by membrane-associated AR. Although the genomic action of AR has been studied in depth, the molecular events governing AR transport to the plasma membrane and the downstream AR signaling cascades remain poorly understood. In this study, we report that AR membrane transport is microtubule-dependent. Disruption of the function of kinesin 5B (KIF5B), but not of kinesin C3 (KIFC3), interfered with AR membrane association and signaling. Co-immunoprecipitation and pulldown assays revealed that AR physically interacts with KIF5B and that androgen enhances this interaction. Furthermore, we show that heat shock protein 27 (HSP27) is activated by membrane-associated AR and that HSP27 plays an important role in mediating AR-mediated membrane-to-nuclear signal transduction. Together, these results indicate that AR membrane translocation is mediated by the microtubule cytoskeleton and the motor protein KIF5B. By activating HSP27, membrane-associated AR potentiates the transcriptional activity of nuclear AR. We conclude that disruption of AR membrane translocation may represent a potential strategy for targeting AR signaling therapeutically in prostate cancer.
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