The spliceosome as a new therapeutic vulnerability in aggressive prostate cancer

Figures & data

Figure 1. The spliceosome represents a therapeutic vulnerability in aggressive prostate cancer (PCa). (a) Five main types of alternative splicing (AS) patterns analyzed in our study. A3, alternative 3ʹ splice sites; A5, alternative 5ʹ splice sites; MX, mutually exclusive exons; SE, exon skipping; IR, intron retention. (b) The spliceosome machinery is disrupted due to mis-expression of splicing-regulatory genes (SRGs) in PCa evolution and contributes to PCa progression via modulating aberrant splicing events. The degree of global AS abnormities aggravates along with disease progression. In addition to treatment responsive emergence (solid arrow) of aggressive PCa (i.e., castration-resistant PCa (CRPC)), some primary PCa with small-cell PCa (SCPC) and/or neuroendocrine PCa (NEPC) features intrinsically resist androgen deprivation therapy (ADT) (dashed arrow), and will progress to advanced stages. Significantly, the tumor AS landscape differs before and after ADT, suggesting a treatment-induced reshaping of global AS pattern that might have contributed to therapy resistance. Collectively, targeting aberrant splicing via spliceosome modulators (e.g., E7107) offers a new way to combat CRPC.