sta-9090 and Mesothelioma

Adaptive resistance to therapy is a hallmark of cancer progression. To date, it is not entirely clear how microenvironmental stimuli would mediate emergence of therapy-resistant cell subpopulations, although a rearrangement of the cancer cell secretome following therapy-induced stress can be pivotal for such a process. Here, by using the highly chemoresistant malignant pleural mesothelioma (MPM) as an experimental model, we unveiled a key contribution of the chaperone HSP90 at assisting a chemotherapy-instigated Senescence-Associated-Secretory-Phenotype (SASP). Thus, administration of a clinical trial grade, HSP90, inhibitor blunted the release of several cytokines by the chemotherapy-treated MPM cells, including interleukin (IL)-8. Reduction of IL-8 levels hampered the FAK-AKT signaling and inhibited 3D growth and migration. This correlated with downregulation of key EMT and chemoresistance genes and affected the survival of chemoresistant ALDH

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cellular Senescence; Cisplatin; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred NOD; Mice, SCID; Pemetrexed; Secretory Pathway; Triazoles