Alternative splicing of ABI1 by enzalutamide treatment drives tumor plasticity in prostate cancer

Prostate cancer affects nearly 1.4 million new patients each year and is the second leading cause of cancer-related deaths. While initial stages of disease are driven by androgen receptor (AR) signaling and treatable with androgen-depravation therapies (ADT) and androgen receptor pathway inhibitors (ARPIs), tumors frequently recur with resistance to these therapies. The development of resistance is driven by tumor plasticity in which mutations, epigenetic changes, and alternative splicing generate phenotypic alterations that allow for adaptations to circumvent AR inhibition.Recent studies have shown that treatment with second generation ARPIs such as enzalutamide may be the very driver of the plasticity leading to its resistance. Enzalutamide treatment has been shown to induce global splicing changes, and promote a high-grade, treatment-resistant, neuroendocrine phenotype. One potential link between the changes in RNA-splicing and the development of a neuroendocrine phenotype is Abelson Interactor 1 (ABI1), a multi-isoform scaffolding protein known to be a regulator of prostate cancer progression. In this study, we aimed to identify how ARPI treatment induces isoform-specific changes in ABI1, and how these changes drive prostate cancer progression. Using a combination of cell line, patient-derived and animal models of prostate cancer, we were able to determine that ARPI treatment deregulates inclusion of ABI1-exon 4, which is critical to ABI1's DNA-binding ability. This dysregulation in turn alters the expression of many genes involved in pathways of transcriptional regulation and stress response during enzalutamide treatment. Taken together, these findings shed new light on the mechanisms behind the development of enzalutamide resistance and provide a novel target in treatment-resistant prostate cancer.