Purpose Malignant mesothelioma (MM) is a devastating disease with a need for new treatment strategies. In the present study we demonstrated the importance of ERK5 in MM tumor growth and treatment. Experimental Design ERK5 as a target for MM therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft SCID mouse models. Results We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in MM cells. ERK5 silencing increased DOX-induced cell death and DOX retention in MM cells. In addition, shERK5 MM lines exhibited both attenuated colony formation on soft agar and invasion of MM cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 MM cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from IP shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis related (IL-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the IP model of tumor growth. Conclusion ; ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in MM patients.

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Malignant mesothelioma (MM) is a neoplastic disease of the pleural, peritoneal or pericardial cavity. Currently, there is no therapy for MM as it is resistant to most of the common chemotherapies and therefore, there is a need for new treatment strategies. In the present study we demonstrated that ERK5 is important in MM tumor growth and can potentially be targeted in combination with the chemotherapeutic drugs for more effective treatment. Human MM cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin to these MM cell lines resulted in further activation of ERK5. ERK5 silencing by small hairpin RNA (shERK5) increased DOX-induced cell death and DOX retention in human MM cells. In addition, shERK5 MM lines exhibited both attenuated colony formation on soft agar and invasion of MM cells in vitro. Most importantly, injection of shERK5 MM cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the IP model of tumor growth, proving our hypothesis that ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in MM patients. This work is supported by Mesothelioma Applied Research Foundation (AS), NIEHS-RO1ES021110 (AS) and T32 ES07122 (BM) grants. Citation Format: Arti Shukla, Jill Miller, Christopher Cason, Mutlay Sayan, Maximilian MacPherson, Stacie Beuschel, Brooke Mossman. Extracellular signal regulated kinase 5 inpathogenesis of malignant mesothelioma. [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 4315. doi:10.1158/1538-7445.AM2013-4315