Abstract 5452: Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: Persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

Abstract

Abstract The value of microRNAs (miRNAs) as novel targets for cancer therapy is now widely recognized. However, no information is currently available on the expression/functional role of miRNAs in diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional treatments, for which the development of new therapeutic strategies is urgently needed. Here, we evaluated the expression and biological effects of miR-34a -one of the most widely deregulated miRNAs in cancer and for which a lipid-formulated mimic is already clinically available- in a large cohort of DMPM clinical samples and a unique collection of in house-developed DMPM preclinical models, with the aim to assess the potential of a miR-34a-based approach for disease treatment. miR-34a was found to be significantly down-regulated in forty-five DMPM clinical specimens and five established cell lines compared to normal peritoneum. miR-34a reconstitution inhibited cell proliferation in a time-dependent manner, though to a different extent and with a different kinetics across individual cell lines. Such a variable antiproliferative effect was paralleled by a different kinetics of apoptosis induction. In addition, miR-34a ectopic expression significantly declined DMPM cell invasion ability and impaired the secretion of angiogenesis-related factors. Phenocopy experiments showed that miR-34a oncosuppressive activities mainly rely on c-MET and AXL down-regulation and the consequent interference with the activation of downstream signaling. Interestingly, a persistent activation of ERK1/2 and AKT in two miR-34a-reconstituted cell lines was found to counteract the antiproliferative and proapoptotic effects of miRNA, yet not affecting its anti-invasive activity. Most importantly, when three subcutaneous/orthotopic DMPM xenograft models were used to examine the impact of miR-34a on tumorigenicity, a significant reduction in tumor take and growth was consistently observed. Our preclinical data, showing impressive inhibitory effects induced by miR-34a on DMPM cell proliferation, invasion and growth in immunodeficient mice, strongly suggest the potential clinical utility of a miR-34a-replacement therapy for the treatment of such a still incurable disease. On the other hand, we provide the first evidence of a potential cytoprotective/resistance mechanism that may arise towards miRNA-based therapies through the persistent activation of receptor tyrosine kinase downstream signaling. Citation Format: Rihan El Bezawy, Michelandrea De Cesare, Marzia Pennati, Marcello Deraco, Paolo Gandellini, Valentina Zuco, Nadia Zaffaroni. Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: Persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5452. doi:10.1158/1538-7445.AM2017-5452