Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.

Clinical cancer research : an official journal of the American Association for Cancer Research

Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in -mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. We observed that mesenchymal -mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal -mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to -mutant lung cancers, as it was also observed in -mutant lung cancers and large datasets, including different cancer subtypes. Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. .