Association of a prostate cancer gastrointestinal transcriptional phenotype as found in clinical mCRPC samples with response to AR-targeted therapy.
Authors: Subramanian Aishwarya , Zhang Meng , Sharifi Marina Nasrin , Moreno Rodriguez Thaidy , Feng Eric , Rydzewski Nicholas Robert , Shrestha Raunak , Zhu Xiaolin , Zhao Shuang , Aggarwal Rahul Raj , Small Eric J. , Ding Chien-Kuang Cornelia , Quigley David Alan , Sjöström Martin 
Published: January 2024

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Background: Prostate cancer is a heterogenous disease, but once metastatic it eventually becomes resistant to all therapies. One mechanism of resistance to AR-targeting therapy is lineage plasticity, where the tumor undergoes a transformation to an AR-indifferent phenotype, most studied in the context of neuroendocrine prostate cancer (NEPC). However, activation of additional de-differentiation programs, including a gastrointestinal (GI) gene expression circuit, has been suggested as alternative methods of resistance. In this study, we aimed to explore the GI prostate cancer phenotype (PCa GI) in a large cohort of metastatic castration-resistant prostate cancer (mCRPC) biopsy samples. Methods: We interrogated a dataset of 634 mCRPC samples with batch effect corrected gene expression data from the West Coast Dream Team (WCDT), the East Coast Dream Team (ECDT), the Fred Hutchinson Cancer Research Center (FHCRC) and the Weill Cornell Medical center (WCM). The WCDT and ECDT had survival data annotated. A gene expression GI score was calculated using the sum of z-scores of genes from a published set of PCa GI defining genes (N=38). Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards regression with survival from time of biopsy to death of any cause as endpoint. Results: The GI score had a bimodal distribution, indicating a distinct set of tumors with an activated GI expression pattern. Approximately 35% of samples were classified as PCa GI which is concordant with prior reports. Liver metastases had the highest median score but when excluding liver samples, 29% of samples still were classified as PCa GI, suggesting a distinct phenotype not exclusive to liver metastases. No correlation was observed between GI score and proliferation, AR signaling, or a NEPC score. Furthermore, no difference in GI score was observed with genomic alterations in AR, FOXA1, RB1, TP53 or PTEN. However, MYC amplified tumors showed higher GI scores (p=0.0001) . Patients with PCa GI tumors had a shorter survival (HR=1.5 [1.1-2.1], p=0.02), but not after adjusting for liver as metastatic site (HR=1.2 [0.82-1.7], p=0.35). Patients with PCa GI low samples had a better outcome after androgen receptor signaling inhibitors (ARSI, abiraterone or enzalutamide) than other therapies (HR=0.2 [0.07-0.54, p=0.002) while there was no difference for PCa GI high samples (HR=1.1 [0.13-8.7], p=0.95, p interaction = 0.049). A differential pathway analysis identified FOXA2 signaling to be upregulated PCa GI high tumors (FDR = 1.7 x 10-28), in addition to high expression of GI related genes, including HNF4G, HNF1A and SPINK1. Conclusions: The PCa GI phenotype is found in clinical mCRPC samples and may represent a distinct biological entity. PCa GI tumors may respond less to ARSI and could offer a strategy to study novel therapeutic targets.