The role of focal adhesion kinase in therapy resistant prostate tumors

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Abstract Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a subgroup of prostate tumors with poor patient outcomes. Beyond systemic chemotherapy and palliative care, no targeted therapy has been successful reflecting our limited knowledge of how NEPC is developed. We have reported a t-NEPC-specific RNA splicing program driven by the neural splicing factor SRRM4, which promotes t-NEPC development. This splicing program has genome-wide impacts on cancer cells as it reprograms the functions of epigenetic modulators, transcriptional factors, and cancer stem cell regulators, resulting in prostate adenocarcinoma cells acquiring neuroendocrine lineage and becoming independent of AR signalling for survival. The FAK (focal adhesion kinase) gene splicing is a part of the t-NEPC splicing program, whereby neural FAK splice variants are highly expressed in t-NEPC. In contrast to the constitutive FAK (FAK-c) splice variant, neural FAKs promote neuroendocrine differentiation and AR-independent tumor growth. Further RNA-seq analysis indicated that these neural FAKs act mainly through a hypoxic transcriptome via HIF-1. Importantly, we found that when tumor cells gain the neural FAK signaling, they become vulnerable to FAK kinase inhibitors. These findings suggest that aberrant RNA splicing of the FAK gene promotes t-NEPC progression and that targeting the FAK signal may provide a new therapeutic option for t-NEPC patients. We have developed four specific aims to test this hypothesis. In Aim 1, we will establish the clinical relevance of neural FAK splicing in association with neuroendocrine carcinoma histology, castrate-resistant prostate cancer progression, tumor metastasis, and patient clinical outcomes. In Aim 2, we will decipher the intrinsic mechanism by which SRRM4 regulates neural FAK splicing, and determine the extrinsic therapy-induced stress conditions that regulate RNA splicing of neural FAKs. In Aim 3, we will characterize several FAK-associated kinase signaling that were known to enhance HIF-1 protein expression through either protein synthesis or protein degradation pathways. We will also employ global proteomic analyses to profile neural FAK interactomes and their activated phosphor- proteomics that promote t-NEPC progression. In Aim 4, we will study whether FAK inhibitors can block neural FAK actions in NEPC cells and test whether FAK inhibitors can be used as a combination therapy to block t- NEPC xenograft growth. In summary, these studies will gain new mechanistic insight into how prostate cancer cells develop therapy- resistance and nominate FAK inhibitors to be potential therapeutics for therapy-resistant prostate tumors.