Abstract 1174: AZD4547 and AZD5363 synergistically inhibit prostate cancer progression by modulating MAPK and AKT activation
Authors: Shu Feng, Michael Ittmann
Journal: Cancer Research (2016)

Abstract Prostate cancer (PCa) is the second most common cancer and the second most common cause of cancer mortality in men in the United States. Multiple approved therapies target the androgen signaling axis in this metastatic disease, however, after advancing to the androgen-independent stage, PCa is unresponsive to androgen ablation therapy and is refractory to further curative treatment. Recent advances have demonstrated that two intracellular signaling pathways promote prostate cancer progression, one is the Fibroblast Growth Factor (FGF) pathway included multiple FGFs and 4 kinds of FGF receptors (FGFR), which remains activated in the cancer cells, the other is the oncogenic PI3K/AKT pathway, which is constantly active due to the loss of an important tumor suppressor gene. Targeted inhibition of FGF and AKT signaling pathways has shown promising both in vitro and in vivo studies. However, FGFR or AKT inhibitor, as a single agent, would result in a reciprocal feedback loop. Therefore, it is imperative that both pathways be targeted simultaneously in the treatment of advanced prostate cancer. In this study, we evaluated the effect of combined treatment of FGFR inhibitor AZD4547 and AKT inhibitor AZD5363 on PCa progression. Proliferation assay shows that AZD4547 just weakly, or not inhibits PCa cell proliferation, AZD5363 significantly inhibits PCa cell proliferation; the combined treatment of AZD4547 and AZD5363 shows similar inhibition effect to AZD5363. Both AZD4547 and AZD5363 inhibit PCa cell anchorage-independent growth and invasion, which are synergistically decrease by the combined treatment. AZD4547 significantly inhibits phosporylation of FGFR1 and FGFR4 in PCa cells; AZD5363 increases FGFR1 and FGFR4 phosphorylation, which was significantly repressed in combined treatment. The activation of FGFR2α, MEK1/2, and Erk1/2 in PCa cells was remarkably inhibited by AZD4547 but increased by AZD5363, and synergistically inhibited by the combined treatment. AKT was hyperphosphorylated by AZD5363 and inhibited by AZD4547. The phosporylation of AKT downstream molecules PRAS40, GSK3β and S6, was slightly decreased by AZD4547 but strongly inhibited by AZD5363 and the combined treatment. Both AZD4547 and AZD5363 suppress STAT3 phosphorylation in PCa cells and the combind treatment shows synergistic inhibition effect. Both AZD4547 and AZD5363 promote AR and PTEN expression at both RNA and protein levels in VCaP and 22RV1cells, and the combination treatment remains the promotion effect. In LNCaP cells, AZD5363, but not AZD4547, stimulates AR mRNA and protein expression, which keep increased in combined treatment. This study provides a preclinical proof of concept that combination of a FGFR inhibitor with an AKT inhibitor has a profound potential to treat PCa. Acknowledgement: This project was supported by the DOD Prostate Cancer Program, PCRP-IDEA-PC120481 (Ittmann), the Prostate Cancer Foundation (Ittmann) Citation Format: Shu Feng, Michael Ittmann. AZD4547 and AZD5363 synergistically inhibit prostate cancer progression by modulating MAPK and AKT activation. [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 1174.