ABSTRACT
The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by the eventual development of acquired resistance. We hypothesize that enhancing apoptosis through combination therapies can eradicate cancer cells and reduce the emergence of drug-tolerant persisters. Through high-throughput screening of a custom library of â¼1,000 compounds, we discover Aurora B kinase inhibitors as potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B inhibition stabilizes BIM through reduced Ser87 phosphorylation, and transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B signaling cascade and thereby engenders hypersensitivity to respective kinase inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition of EGFR and Aurora B not only efficiently eliminates cancer cells but also overcomes resistance beyond EMT.
Subject(s)
Acrylamides/pharmacology , Aniline Compounds/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Apoptosis Regulatory Proteins/metabolism , Aurora Kinase B/antagonists & inhibitors , Bcl-2-Like Protein 11/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Drug Screening Assays, Antitumor , Drug Synergism , Epithelial-Mesenchymal Transition/drug effects , Gene Expression Regulation, Neoplastic/drug effects , High-Throughput Screening Assays , Humans , Lung Neoplasms/drug therapy , Proto-Oncogene Proteins/metabolism , Small Molecule Libraries/pharmacologyABSTRACT
Immunomodulatory molecules produced by helminth parasites are receiving much attention recently as novel therapeutic agents for inflammation and autoimmune diseases. In this study, we show that macrophage migration inhibitory factor (MIF) homologue from the filarial parasite, Wuchereria bancrofti (rWbaMIF-2), can suppress inflammation in a dextran sulphate sodium salt (DSS)-induced colitis model. The disease activity index (DAI) in DSS given mice showed loss of body weight and bloody diarrhoea. At autopsy, colon of these mice showed severe inflammation and reduced length. Administration of rWbaMIF-2 significantly reduced the DAI in DSS-induced colitis mice. rWbaMIF-2-treated mice had no blood in the stools, and their colon length was similar to the normal colon with minimal inflammation and histological changes. Pro-inflammatory cytokine genes (TNF-α, IL-6, IFN-γ, IL-1ß, IL-17A and NOS2) were downregulated in the colon tissue and peritoneal macrophages of rWbaMIF-2-treated mice. However, there were significant increases in IL-10-producing Treg and B1 cells in the colon and peritoneal cavity of rWbaMIF-2-treated mice. These findings suggested that rWbaMIF-2 treatment significantly ameliorated the clinical symptoms, inflammation and colon pathology in DSS given mice. This immunomodulatory effect of rWbaMIF-2 appeared to be by promoting the infiltration of Treg cells into the colon.