Abstract 4100: Androgen receptor signaling dysregulates the mitotic checkpoint to mediate docetaxel resistance in castration-resistant prostate cancer

Abstract

Abstract Prostate cancer is the most commonly diagnosed and the second most deadly cancer in American men. Despite dramatic initial responses to androgen deprivation therapy (ADT), the disease inevitably progresses to castration-resistant prostate cancer (CRPC), frequently driven by reactivation of the androgen receptor (AR). CRPC remains incurable: current treatment options offer only modest survival benefit and resistance can occur rapidly. Docetaxel remains the standard first line treatment for patients with metastatic CRPC, however, nearly all CRPC patients become refractory due to drug resistance. Interestingly, when docetaxel is deployed with ADT in metastatic hormone-sensitive prostate cancer (mHSPC), survival is improved significantly more than for CRPC. Since AR is frequently reactivated in CRPC, we hypothesized that altered AR signaling influences docetaxel sensitivity in CRPC. Docetaxel binds to microtubules, disrupting microtubule dynamics and activating the mitotic checkpoint pathway, a complex mechanism that maintains mitotic fidelity and prevents chromosome instability. In an analysis of primary prostate and metastatic tumors, we observe differential copy number and expression of several mitotic checkpoint-regulating genes, suggesting reprogramming of the mitotic checkpoint in metastatic CRPC. Furthermore, our in vitro studies demonstrate a novel link between AR activation and mitotic checkpoint signaling. In hormone-sensitive LNCAP cells, AR activation (by addition of androgen) attenuates mitotic checkpoint activation in response to docetaxel, leading to mitotic slippage and resistance to docetaxel. Cell-cycle analysis under these conditions demonstrates loss of G2/M arrest, decreased apoptosis, and an increased tetraploid cell population. In addition, the AR-activated LNCAP cells show significantly fewer mitotic errors (i.e. lagging chromosomes) and an increased number of multi-nucleated cells in response to docetaxel compared to non-hormone treated cells. Importantly, analysis of CRPC cell lines C4-2 and 22Rv1 demonstrate results concordant with the hormone-treated LNCAP cells, suggesting AR signaling can drive mitotic progression to escape cell death. Finally, we determined that microtubule stabilization is critical for AR-mediated checkpoint inhibition and identified several kinase targets that force mitotic arrest and sensitize cells to docetaxel. Our results reveal that targeting key kinases that regulate mitotic checkpoint activation is a novel therapeutic strategy to overcome docetaxel resistance and improve outcomes for patients with lethal prostate cancer. Citation Format: Amanda Pilling, Clara Hwang. Androgen receptor signaling dysregulates the mitotic checkpoint to mediate docetaxel resistance in castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4100.