Abstract 38: ERK5 inhibitor XMD8-92 for malignant mesothelioma treatment: A preclinical study

Abstract

Abstract Malignant mesothelioma (MM) is an aggressive cancer in dire need of successful treatment. We are first to demonstrate that Extracellular signal regulated kinase 5 (ERK5) plays an important role in MM pathogenesis (Clinical Cancer Research, 19, 2013). In this study we used genetically manipulated (ERK5 inhibited) MM cell lines to show that MM tumorigenesis is influenced by ERK5. In the present study we used recently discovered specific ERK5 inhibitor (XMD8-92) to show that it regulates MM tumor growth both in vitro and in vivo. First, we show that XMD8-92 inhibits ERK5 phosphorylation in 3 out of 4 MM cell lines showing constitutive activation of ERK5. Next, time and dose dependent study demonstrated significant cytotoxicity of XMD8-92 on 3 different MM cell lines. We also showed that soft agar colony forming efficiency of H2373 MM cells was significantly reduced in response to XMD8-92 treatment. Furthermore, in vivo studies using syngeneic mouse model of intraperitoneal mesothelioma showed that XMD8-92 treatment (50 mg/kg, ip, 1x daily for 3 weeks) resulted in significant decreases in tumor weights as compared to vehicle treated mice. Total and differential cell counts in peritoneal lavage fluid (PLF) were also inhibited by XMD8-92 suggesting the role of inflammation in MM tumor growth and their inhibition by ERK5 inhibitor. Cytokine profile assessment in PLF demonstrated the reduced levels of VEGF and IL-6 in XMD8-92 treated animals as compared to control animals receiving saline. FGF2, MCP-1, G-CSF, KC and RAGE levels were, however, not significantly impacted by the ERK5 inhibition. Taken together these data suggest that ERK5 inhibitor/ERK5 inhibition could be used for inhibiting the growth of MM tumors. Currently we are exploring the role of XMD8-92 alone as well as in combination with chemotherapeutic drugs for the treatment of MM using various mouse models. We are also exploring the role(s) of ERK5 inhibitor in inflammasome regulation by chemotherapeutics. This work is supported by NIEHS RO1 ES021110 and VCC/LCCRO grants. Citation Format: Arti Shukla, Joyce Thompson, Anurag Shukla, Alan Leggett, Maximilian MacPherson, Stacie Beuschel. ERK5 inhibitor XMD8-92 for malignant mesothelioma treatment: A preclinical study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 38. doi:10.1158/1538-7445.AM2015-38