The mitogen-activated protein kinase (MAPK) pathway is involved in a broad range of cellular processes that include proliferation, survival, apoptosis, and cellular differentiation. MAPK has also been shown to increase the transcription of androgen-dependent (AR) genes, independently of androgens by phosphorylation of the AR or its cofactors. Thus, MAPK signal inhibition has the potential to be a therapeutic target for prostate cancer. To determine the clinical benefit of MAPK inhibition, we used the highly selective MEK inhibitor, AZD6244, in a prostate-specific PTEN-conditional knockout mouse model of prostate cancer. In this model, prostate tumors from mice exhibit increased levels of p-Erk1/2 expression that correlates with tumor progression. Acute pharmacodynamic responses, after a single dose of AZD6244, showed a strong inhibition of Erk1/2 phosphorylation that was maintained for at least 24 hours after drug administration. Levels of cellular proliferation decreased, and apoptosis was induced shortly after the administration of AZD6244. However, apoptosis was suppressed after 8 hours. To further characterize the responses to MAPK signal inhibition, we examined the activity of downstream molecules of the PI3K/Akt and JAK/STAT3 signaling pathways. While PI3K/Akt activity decreased mildly, activation of JAK/STAT3 was transiently but strongly increased. To determine tumor responses to chronic administration of AZD6244, Pten-mutant mice harboring prostate tumors were treated with AZD6244 for 4 a period of 4 weeks. 2-D morphometric analysis of tumor surface area showed a reduction of 10.9% (P =0.035) in treated mice. Furthermore, inhibition of p-Erk was maintained and tumor cell proliferation was reduced by 25.24% (P =0.005). The apoptotic index increased from 3.9% in controls to 7.2% (P=0.004) in mice receiving AZD6244. Our findings suggest that inhibition of MAPK signaling can contribute to decreased tumor progression and may represent a promising therapeutic alternative.

Citation Format: Hirotsugu Uemura, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Marco A. De Velasco. Preclinical responses of the MEK inhibitor AZD6244 in a genetically modified mouse model of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 916. doi:10.1158/1538-7445.AM2013-916