Abstract B013: KLF5 drives basal cell identity to promote prostate cancer lineage plasticity

Abstract The purpose of this study was to characterize the phenotypes and drivers of therapy-induced lineage plastic castration resistant prostate cancer (CRPC). Since the majority of primary prostate cancer presents with a luminal cell identity, which relies on androgen receptor (AR) signaling for growth and survival, AR-targeted therapies have become an effective method of slowing progression. However, CRPC cells can develop resistance through reduced or lost dependence on AR. These cells can transition their identity to neuroendocrine CRPC (NEPC), which lacks AR and expresses neuroendocrine lineage specific markers like chromogranin A. More frequently, these cells display transition to a cell identity that lacks AR and neuroendocrine markers and has been termed double-negative CRPC (DNPC). Identifying effective therapeutic targets to treat or prevent DNPC remains a significant clinical challenge. By utilizing prostate cancer cell lines, patient derived xenografts (PDX), and publicly available data from clinical CRPC specimens, we have identified an upregulation in basal cell identity in a subset of CRPC in response to AR-targeted therapies. Additionally, we show that the stem cell transcription factor KLF5, which is highly expressed in healthy prostate basal cells, is uniquely upregulated in CRPC subtypes displaying basal cell identity. In a cell line model of DNPC, we found that knockdown of KLF5 decreased the expression of genes that define basal cell identity. From these results, we conclude that AR-targeted therapies, while effective at targeting luminal-like adenocarcinoma, promote upregulation of KLF5 which can drive a basal cell identity and AR independence. These studies nominate KLF5 signaling as a potential therapeutic target to block the emergence of basal identity, inhibit prostate cancer lineage plasticity, and increase the durability of AR-targeted therapies. Citation Format: Samuel P. Pitzen, Yinjie Qiu, Sarah Munro, Scott M. Dehm. KLF5 drives basal cell identity to promote prostate cancer lineage plasticity [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B013.