Abstract 1092: Defining the molecular phenotypes of metastatic castration-resistant prostate cancer sensitive to FGF pathway inhibition

Background: Widespread and long-term use of first-and second-line androgen-deprivation therapy (ADT) is changing the molecular and phenotypic landscapes of prostate cancer. Observations made through our longstanding rapid autopsy and patient-derived xenograft (PDX) programs at the University of Washington support a shift in metastatic castration-resistant prostate cancer (mCRPC) towards androgen receptor (AR)-null phenotypes, such as neuroendocrine (NEPC) and double negative (DNPC). Currently, there are no effective therapies for AR-null mCRPC. We showed previously that DNPC (AR-null, NE-null) bypasses AR-dependence through fibroblast growth factor (FGF) signaling. However, the role of the FGF pathway in other molecular mCRPC subtypes remains to be determined. Methods and Results: Here, we define four mCRPC subtypes that can be categorized by the presence or absence of functioning AR or RE1-silencing transcription factor (REST). Transcriptomic analysis of mCRPC specimens showed that AR and REST activity define four emerging mCRPC phenotypes: adenocarcinoma (AR+/REST+), amphicrine (tumor cells that co-express AR and NE markers, AR+/REST-), DNPC (AR-/REST+) and NEPC (AR-/REST-). Immunohistochemistry of mCRPC and PDX models for AR, prostate specific antigen, synaptophysin, chromogranin, and other clinically relevant markers accurately reflected the AR/REST transcriptomic signature classifications. Furthermore, loss of REST activity can, at least in part, be attributed to alternative splicing of REST mRNA by serine/arginine repetitive matrix protein 4 (SRRM4), leading to the translation of a truncated REST protein. PCR analysis of mCRPC identified the REST splice variant exclusively in amphicrine and NEPC specimens. RNA sequencing/GSEA, qPCR and immunoblot analyses determined that overexpression of SRRM4 or siRNA knockdown of REST in C4-2B (AR+) and PC-3 (AR-) prostate cancer cells promotes expression of neuroendocrine markers. Finally, we are conducting preclinical testing of the FGFR inhibitor CH5183284 in multiple PDX models representing the four mCRPC subtypes described above to delineate the impact of FGF pathway inhibition in all mCRPC subtypes. Conclusions: Our data highlight the importance of AR and REST transcriptional programs in maintaining phenotypic stability in mCRPC and explain the phenotypic heterogeneity of mCRPC in the post-abiraterone/enzalutamide era. Understanding the mCRPC subtypes that depend on the FGF pathway for survival and proliferation will inform treatment and lead to the development of novel therapies for advanced disease. Citation Format: Mark P. Labrecque, Lisha G. Brown, Ilsa M. Coleman, Lawrence D. True, Lori Kollath, Bryce Lakely, Yu C. Yang, Holly M. Nguyen, Eva Corey, Peter S. Nelson, Colm Morrissey. Defining the molecular phenotypes of metastatic castration-resistant prostate cancer sensitive to FGF pathway inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1092.