Abstract 5502: Androgen blockade confers sensitivity to PIKfyve inhibition in prostate cancer
Authors: Qiao Yuanyuan , Yee Sarah Nicole , Cheng Caleb , Zheng Yang , Luo Jie , Bao Yi , Jiang Xia , Cao Xuhong , Zhang Yuping , Chinnaiyan Arul M. 
Published: April 2023

In 2022, 268,490 American men will be diagnosed with prostate cancer and 34,500 men will succumb to its complications. Despite significant advances in prostate cancer treatment over the past few decades, resistance inevitably develops with certain therapies, including second-generation anti-androgens; new case numbers also keep climbing each year, leading to one in every eight men being diagnosed with prostate cancer during his lifetime. Therapies targeting the androgen receptor (AR) as the main driver of prostate cancer lead to various mechanisms of resistance and promote disease progression to castration-resistant prostate cancer (CRPC), which has a median survival of only 9-36 months. Amongst recurrent CRPC, 17%-30% of patients develop neuroendocrine prostate cancer which is characterized by it’s unique histopathology and loss of AR signaling. Our previous study demonstrated that autophagy blockade via PIKfyve inhibition has preferential cytotoxicity in neuroendocrine prostate cancer over prostatic adenocarcinoma leading us to further validate the role of AR signaling in PIKfyve blockade sensitivity. Thus, we postulate that androgen signaling attenuates the dependency of prostate cancer on PIKfyve, while on the other hand, AR antagonist may sensitize prostatic adenocarcinoma to PIKfyve inhibition.

Method

Several AR positive prostate cancer cell lines were examined for combinational effect of AR antagonists and PIKfyve inhibitors in vitro with synergistic scores calculated. A pair of isogenic LNCaP cells with proficient AR signaling (LNCaP-parental) and deficient AR signaling (LNCaP AR-null) were used for PIKfyve inhibitor sensitivity. Additionally, two AR positive cell line-derived xenografts (LNCaP and VCaP) were established in vivo for combinational assessment of AR antagonist Enzalutamide and PIKfyve inhibitor ESK981. Tumor growth inhibition were monitored pre- and post- treatments. On target assessment were examined for downstream targets of AR antagonist, as well as LC3-lipidation for PIKfyve inhibition. In situ cell death events of treated tumors in vivo were evaluated by TUNEL assay.

Conclusion

We have discovered that inhibition of AR signaling by Enzalutamide demonstrated strong synergistic anti-proliferative effects with PIKfyve inhibition by ESK981. Similarly, using a pair of isogenic LNCaP cells with proficient (LNCaP-parental) and deficient AR signaling (LNCaP AR-null), we showed that loss of AR signaling notably increased the sensitivity of LNCaP cells to PIKfyve inhibition. Concurrent treatment with Enzalutamide and ESK981 in vivo triggered greater tumor inhibition and more robust in situ cell death events than either agent alone. Collectively, PIKfyve may have a context-dependent role in AR signaling-dependent and -independent prostate cancer, so that by co-targeting AR signaling and PIKfyve, therapeutic outcome of prostate adenocarcinoma can be improved.

Citation Format: Yuanyuan Qiao, Sarah Nicole Yee, Caleb Cheng, Yang Zheng, Jie Luo, Yi Bao, Xia Jiang, Xuhong Cao, Yuping Zhang, Arul M. Chinnaiyan. Androgen blockade confers sensitivity to PIKfyve inhibition in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5502.