Abstract 2754: Uncovering the role of TEADs in treatment induced small cell or neuroendocrine prostate cancer

Abstract

Abstract Study Purpose: Determine the role of the transcription factor TEAD1 in promoting the neuroendocrine phenotype in castration-resistant prostate cancer (CRPC). Experimental Procedures: We quantitated YAP-pathway associated transcripts, protein abundance, and splicing events in androgen receptor (AR) positive prostate adenocarcinoma (ARPC) and small cell or neuroendocrine prostate cancer (SCNPC) using RNAseq, scRNAseq, qPCR, immunohistochemistry (IHC), CpG methylation, and western blot analyses on patient samples, patient-derived xenograft (PDX) models, and cell lines. In addition, we tested the impact of the pharmacological inhibition and knockdown of proteins and genes associated with TEAD1 activity in ARPC and SCNPC cell lines on TEAD1 expression, cell number, and tumor cell differentiation. Results: Transcriptomic analyses revealed a decrease in YAP1, TAZ, LATS2, and TEAD2 and an increase in LATS1, TEAD1 and RBFOX2 transcript levels in SCNPCs compared to ARPCs in SU2C, rapid autopsy metastases, and PDX models. Similar results were observed in ARPC and SCNPC cancer cell lines, in the transplantable LTL331 prostate cancer transdifferentiation model, and scRNAseq of liver CRPC metastases from patients. The decrease in YAP1, TEAD2 and LATS2 expression correlates with increased methylation and the increase in TEAD1 correlates with decreased methylation in SCNPC PDX models, suggesting epigenetic control. The changes in YAP and YAP-associated proteins (most importantly TEAD1) at the epigenetic and transcriptional level were confirmed by IHC analysis comparing ARPC to SCNPC PDX models. Of the four TEAD proteins, TEAD1 expression was increased, with a concomitant decrease in TEAD2 and TEAD3, whereas low levels of TEAD4 transcript are maintained in the SCNPC phenotype. Notably, RBFOX2 was increased in the SCNPC datasets. RBFOX2 is a pre-RNA splicing regulator that promotes the inclusion of exon 6 in TEAD1 mRNAs associated with increased TEAD1 activity. The RBFOX2 spliced TEAD1 was observed in the SCNPC PDX models, while not detected in the ARPC PDX models. Conclusions: The conversion of ARPC to SCNPC involves the loss of transcriptional regulators: AR, YAP, and REST inactivation in SCNPC. It also involves the expression of ASCL1 or NEUROD1, well described master regulators that are implicated in the conversion to and maintenance of the SCNPC phenotype. Our work suggests TEAD1 is another transcriptional regulator in SCNPC that warrants further investigation. Citation Format: Lisha G. Brown, Ilsa M. Coleman, Tony L. Chu, Daniel W. Lin, John K. Lee, Erolcan Sayar, Lawrence D. True, Ruth Dumpit, Eva Corey, Peter S. Nelson, Michael C. Haffner, Colm Morrissey. Uncovering the role of TEADs in treatment induced small cell or neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2754.