Abstract
Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. This review looks into the current and future role of preclinical models to understand resistance to androgen receptor-targeted therapies. Increasing knowledge on this resistance will greatly improve insights into tumor pathophysiology and future treatment strategies in prostate cancer.
Highlights
The androgen receptor (AR) is the main driver of proliferation in prostate cancer (PCa) cells, and is an important therapeutic target [1,2]
Genetically-Engineered Mouse Models (GEMM) of different pathways that lead to treatment resistance in humans have been recreated, of which the most commonly altered mechanisms are represented in Table 2 [31,32]
Activated STAT3 is found in 95% of CRPC metastases [92], and STAT3 activation is increased upon enzalutamide treatment in LNCaP cells [88,93]
Summary
The androgen receptor (AR) is the main driver of proliferation in prostate cancer (PCa) cells, and is an important therapeutic target [1,2]. LNCaP is a cell line derived from a lymph node metastasis It harbors a T877A AR mutation, with ligand promiscuity and has only a modest potential to form xenografts in nude mice [9]. PCa cell lines play an important role in investigating the plethora of AR resistance mechanisms Such resistance to AR signaling inhibitors may pre-exist in the patient (de novo resistance) or may develop upon treatment of the patient (acquired resistance). Genome-wide CRISPR-Cas screenings allowed the discovery of novel resistance mechanisms [24] While these cell lines certainly have their place in the preclinical research landscape, they do not reflect all aspects of the heterogeneous primary tumor biology. The complex chromosomes of LNCaP (87 chromosomes), PC3 (58/113), and DU145 (62 chromosomes) have structural alterations of multiple chromosomes (1, 2, 4, 6, 10, 15, and 16) [25]
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