Abstract 1347: NTRK1/TRKA as a therapeutic target in castration resistant prostate cancer

Abstract

Abstract Treatment options remain limited for men with castration resistant prostate cancer, with current chemotherapy offering mainly palliative benefits. Thus, there is an urgent need to identify new targets for therapeutic intervention in men who have progressed on anti-androgen therapy. We have compiled a panel of 20 prostate cancer cell lines that has been extensively characterized at the molecular level that enables us to perform high throughput drug and siRNA screens to identify novel therapeutic targets. We performed an siRNA screen targeting kinases using eight representative lines, both in the presence and absence of the anti-androgen MDV3100. Knockdown of NTRK1 (TRKA) significantly inhibited growth in 4/8 of the cell lines tested. To confirm this, we screened the entire panel of cell lines with the inhibitor CEP-701, which targets FLT3, JAK2, and TRK-A/B/C. CEP-701 showed GI50 values (dose required to inhibit growth by 50%) less than 400 nM in 8/20 cell lines. Since this drug had already been tested in clinical trials for prostate cancer and the trials were discontinued due to lack of PSA decline, we looked for other drugs that also inhibit TRKA. Both BIBF-1120 and GSK-1363089 are also known to inhibit TRKA, but neither have been tested in prostate cancer expressing TRKA. We tested GSK-136089 in a subset of 9 prostate cell lines, and found that 4/9 lines reached GI50 at 1 uM or less, including AR mutant or null lines such as 22rv1 and PC3 that are non-responsive to MDV3100. Additional tests with BIBF-1120 and GSK-1363089 are underway. These data suggest that NTRK1 may be a potential target for patients with castration resistant prostate cancer. Citation Format: James E. Korkola, Moqing Liu, Rebecca Smith, Tiera Liby, Joe W. Gray. NTRK1/TRKA as a therapeutic target in castration resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1347.