Abstract 3837: Bumped kinase inhibitor 1553 selectively inhibits androgen receptor positive prostate cancer

Abstract

Abstract BACKGROUND: Prostate cancer (PCa) is the second most common cancer in men and one of the leading causes of cancer death. Resistance to current PCa therapies, including androgen deprivation, occurs in almost all patients leading to development of castration resistant prostate cancer (CRPC). Resistance is associated with expression of splice variants of the androgen receptor (AR-Vs) that are constitutively active. The intrinsically disordered N-terminus of the AR/AR-Vs makes targeting the AR-Vs difficult. Thus, therapies that indirectly target the AR by inhibiting factors important in regulating AR levels and activity may be the most successful against inhibiting the constitutively active AR variants. Kinases have been shown to be important in regulating the AR, thus kinase inhibitors have the potential to inhibit androgen receptor signaling and function. OBJECTIVE: To demonstrate that our lead kinase inhibitor targets and inhibits AR positive CRPC. RESULTS: Bumped kinase inhibitors designed at the University of Washington are based on a pyrazolopyrimidine backbone, with R1 and R2 groups that confer a “bump” thereby preventing the BKIs from binding to most human kinase ATP binding pockets. While the majority of BKIs do not have activity against CRPC, a subset have activity against AR+ PCa lines, including CRPC lines expressing AR-Vs, but with no activity against AR negative PCa lines or a broad range of other human cell lines. We next examined the effects of our lead BKI compound (1553) on AR expression, phosphorylation, and function. BKI-1553 blocked transactivation activity of AR as judged by the reporter assays using an ARE-luciferase construct. Expression of canonical AR target genes was downregulated in LNCaP cells treated with BKI-1553. Westerns demonstrated a decrease in total AR 4 and 24 hours after treatment with BKI-1553. Levels of phospho-Serine81on the AR, which is critical for AR activity, were decreased even further than total AR by 4 hours after treatment. Thus, AR signaling appears to constitute BKI-sensitive components. We then decided to examine the effect of BKI-1553 on in vivo tumor growth. Toxicity studies demonstrated that it was non-toxic in mice at oral doses that achieved therapeutic levels. In vivo treatment with BKI-1553 significantly decreased growth of a castrate-sensitive patient-derived PCa xenograft and a castration-resistant PCa cell line (LuCaP35, p < 0.01 and LNCaP95, p < 0.005, respectively). SUMMARY: Our lead bumped kinase inhibitor, BKI-1553, selectively inhibits the growth of prostate cancer cells that express full-length AR and/or AR-Vs. BKI-1553 reduced not only cell proliferation, but decreased levels of AR and AR variants, decreased pSer81 levels, and decreased activation of AR-regulated promoters. Since the majority of CRPCs are AR driven, our targeted BKIs could be a novel therapy for cancers that are resistant to currently available therapies. Citation Format: Takuma Uo, Shihua Sun, Kathleen Haugk, Kathryn Soriano Epilepsia, Mamatha Damodarasamy, Matthew Hulverson, Wesley VanVoorhis, Kayode K. Ojo, RamaSubbaRao Vidadala, Dustin Maly, Stephen Plymate, Cynthia C. Sprenger. Bumped kinase inhibitor 1553 selectively inhibits androgen receptor positive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3837.