Abstract LB017: Preclinical validation of HOXB13 as a therapeutic target in prostate cancer

Abstract HOXB13 is a lineage-dependent transcription factor involved in the growth of androgen-independent prostate cancer cells. It promotes cell proliferation in low-androgen environments by activating E2F signaling and inhibiting the expression of the p21 tumor suppressor. Its expression is restricted to prostate cancer and largely absent from normal tissue making it an intriguing oncology target. Furthermore, it is reported that HOXB13 is a regulator of the androgen receptor (AR), and the HOXB13 ChIP-seq signature overlaps with those of full-length AR and the AR splice variant lacking the AR ligand binding domain known as AR-V7. Thus, HOXB13 represents an alternative target in AR amplified and/or ARV7 prostate cancer and could combine well with existing or emerging therapies targeting AR. Here we describe both in vitro and in vivo experiments that further validate HOXB13 as a promising target in prostate cancer. Our work demonstrates that genetic knockdown of HOXB13 exhibits similar anti-proliferative activity to knockdown of AR across multiple prostate cancer cell lines. Furthermore, dox-induced knockdown of HOXB13 in the 22RV1 CDX model results in tumor stasis. These data suggest that HOXB13 can play a significant role in prostate cancer progression. Interestingly, HOXB13 is also expressed in AR negative (AR-) prostate tumors as well. Genetic knockdown of HOXB13 in the AR- PC3 cell line results in loss of cell viability, implying that HOXB13 also possesses an AR independent effect. To further elucidate the downstream targets affected by HOXB13, we utilized RNAseq following genetic knockdown of HOXB13 or AR in several prostate cancer cell lines. Our analysis reveals that loss of HOXB13 yields deeper downregulation of cell cycle pathway genes compared to AR. This suggests that cell cycle downregulation could be a key mechanism by which loss of HOXB13 exerts its antitumor effect in AR+ and AR- prostate cancer. Overall, this study is the first to our knowledge where a head-to-head comparison has been made between AR and HOXB13 across multiple cell line models. With limited treatment options available for prostate cancer patients, this finding opens the possibility of targeting HOXB13 as a new therapeutic option. Citation Format: Meera Shah, Tannu Suwal, Menaka Biala, Lisa Deaton, Cynthia Cienfuego, Art Nasamrans, Jose Juarez, Hedy Chan, Ryan Sullivan, Jisoo Park, Ansgar Brook, Andrew Schumacher, Jun Liu, Jake Haling. Preclinical validation of HOXB13 as a therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB017.