Malignant mesothelioma is a devastating, therapy-resistant cancer most commonly seen in individuals with a history of exposure to asbestos. Asbestos is both a powerful inducer of necrotic death in mesothelial cells and a potent activator of pro-inflammatory gene expression in macrophages. As necrotic cells are themselves well- established inducers of inflammation, these two asbestos-induced events - necrosis in mesothelial cells and pro-inflammatory gene induction in macrophages - are believed to collaborate in an amplificatory cycle that eventually culminates in mesothelioma. We have made the exciting discovery that both asbestos-induced cell necrosis and inflammatory gene induction are dependent on two kinases, receptor-interacting protein (RIP) 1 and RIP3. Importantly, both RIP1 and RIP3 are druggable targets, and we have identified several potent RIP1/3 single- and dual-kinase inhibitors, including an FDA-approved anti-cancer drug, thus offering a unique opportunity for accelerated development of new chemopreventive and chemotherapeutic agents for malignant mesothelioma. We have also established cutting-edge murine models of RIP1 and RIP3 kinase deficiency, as well as an in vivo model of asbestos-driven mesothelioma progression that faithfully mimics the human disease. Together, these new inhibitors and mouse models of malignant mesothelioma allow us to set forth the following three goals for this proposal. First, we will identify the source (i.e., macrophages vs. non-phagocytic cells), relative contribution (RIP1 vs. RIP3), and stage (early vs. late) of pathogenic RIP1/3 kinase activity during asbestos-induced tumorigenesis. Second, we will evaluate activity and pharmacological properties of a panel of single- and dual-targeting RIP1/RIP3 inhibitors in vitro and select the most promising molecules for preclinical testing of RIP1/3 kinase blockade in mesothelioma. We will also determine the crystal structures of RIP1 and RIP3 in complex with a potent new RIP1/3 dual-kinase inhibitor to repurpose this inhibitor (a current FDA-approved anti-cancer agent) for use in mesothelioma. Third, we will test if inhibiting RIP1/3 kinase activity in vivo has preventiv and/or therapeutic efficacy in a preclinical mouse model of malignant mesothelioma. These multipronged studies, proposed by three highly experienced investigators with complementary expertise, represent a comprehensive approach bringing together immunology, genetics, and synthetic chemistry to yield both novel basic insights into mesothelioma development and translational opportunities in malignant mesothelioma prevention/therapy. Successful completion of these Aims has the potential to radically transform approaches for the prevention and treatment of this incurable cancer.