Splice Variants Articles

Drug resistance and especially cross-resistance are the most important problems of therapy of prostate cancer. Drug resistance mechanisms, including ligand-dependent (requiring the presence of androgens in the cell) and independent (not requiring androgens) ones, are reviewed.

The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions.

Androgen receptor (AR) splice variants have been clinically associated with progressive cancer, castration-resistance, and resistance to AR antagonists and androgen synthesis inhibitors. AR variants can be generated by genomic alterations and alternative splicing, and their expression is androgen-regulated.

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.

The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer.

Multiple studies have demonstrated the importance of androgen receptor (AR) splice variants (SVs) in the progression of prostate cancer to the castration-resistant phenotype and their utility as a diagnostic.

While androgen ablation remains a mainstay for advanced prostate cancer therapy, nearly all patients will inevitably develop disease escape with time. Upon the development of castration-resistant prostate cancer, other androgen-axis-targeted treatments may be added in an effort to starve the disease of its androgen signaling.

Every year, prostate cancer is diagnosed in millions of men. The androgen receptor's (AR) unchecked activation is crucial in causing the development and progression of prostate cancer. Second-generation anti-androgen therapies, which primarily focus on targeting the Ligand Binding Domain (LBD) of AR, are effective for most patients.

Over the last ten years, two new-generation hormonal drugs and two chemotherapeutic agents have been approved for the treatment of metastatic castration-resistant prostate cancer. Unfortunately, some patients have primary resistance to them and the others eventually develop secondary resistance.