Abstract 1458: Targeting fibroblast growth factor receptors in castration-resistant prostate cancer

Abstract

Abstract Background: Androgen receptor (AR) pathway inhibition remains the cornerstone for prostate cancer therapies. Although AR signaling inhibitors (ARSI), such as enzalutamide (ENZ) and abiraterone (ABI), extend survival in recurrent and castration-resistant prostate cancer (CRPC), durable complete responses are rare. Bypass mechanisms employed by metastatic CRPC include amplification of AR and AR splice variants in AR-high CRPC (ARPC) and conversion to AR-null phenotypes, such as double-negative prostate cancer (DNPC) and small cell or neuroendocrine prostate cancer (SCNPC). We showed previously that DNPC bypasses AR-dependence through fibroblast growth factor (FGF) signaling. However, the utility of targeting the FGF pathway in other molecular subtypes of CRPC remains to be determined. Methods: RNASeq was conducted on 98 patient metastases, 18 LuCaP patient-derived xenograft (PDX) models and CRPC cell lines. Sensitivity to ARSI and FGFR inhibitors (FGFRi) alone or in combination in cell lines (C4-2B, VCaP, 22Rv1, DU145 and NCIH660) or ex vivo PDX tumor cells (10 ARPC models, 2 DNPC models, and 6 SCNPC models) was measured through CellTitre Glo assays. On-target effects of inhibitors were assessed through immunoblot and qPCR. In vivo efficacy of FGFRi in ARPC and SCNPC was conducted using LuCaP PDX models. Results: Interrogation of FGF pathway activity and FGFR expression using RNASeq and FGF signature scores in CRPC metastases, LuCaP PDX models and CRPC cell lines revealed upregulated FGF pathway activation in AR-null DNPC and SCNPC and in subsets of ARPC. In vitro/ex vivo analysis of FGFRi (erdafitinib, CH5183284 and rogaratinib) demonstrated robust growth suppression in DNPC and moderate growth suppression in SCNPC. In vivo CH5183284 administration recapitulated the growth suppression observed in vitro for SCNPC LuCaP 93 and LuCaP 173.1 but not for SCNPC LuCaP 49. Furthermore, in vitro/ex vivo analysis of AR-expressing CRPC models determined that combination ARSI (ENZ, ABI or darolutamide) with FGFRi was superior to ARSI or FGFRi monotherapies in a subset of models. Immunoblot and qPCR analyses verified that FGFRi-mediated growth suppression occurs through inactivation of the MAPK/MEK and ERK signal transduction cascade in AR-expressing CRPC. Finally, ARPC LuCaP PDX models treated with combination ARSI and FGFRi showed significant tumor growth inhibition compared to control and monotherapy groups in vivo. Analysis of resistance mechanisms to FGFRi therapy are ongoing. Conclusions: The emergence of bypass mechanisms that subvert AR-dependence in mCRPC highlights a need for novel therapeutic strategies. Our data nominate the FGF pathway as an actionable target in diverse phenotypes of treatment-refractory mCRPC. Citation Format: Mark P. Labrecque, Lisha G. Brown, Ilsa M. Coleman, Bryce Lakely, Holly M. Nguyen, Eva Corey, Peter S. Nelson, Colm Morrissey. Targeting fibroblast growth factor receptors in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1458.