Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors

Abstract

Epithelial-to-mesenchymal transition (EMT) is a cellular plasticity program that can confer invasiveness, dissemination, and therapy resistance to cancer cells. Although inhibitors of this cellular process are expected to work as good “partners” for chemotherapy, immunotherapy or targeted therapy drugs, direct targeting of the EMT phenomenon is, in most cases, pharmacologically challenging. The objective of this work was twofold: On the one hand, to determine if the mere process of EMT is sufficient to foster the resistance of lung cancer cells to various generations of ALK tyrosine kinase inhibitors (TKIs); on the other hand, to test the capacity of the natural compound silibinin to re-sensitize lung cancer cells that gained a mesenchymal phenotype to the anti-tumor activity of ALK–TKIs. Our findings show that not all ALK-aberrant lung cancer cells exhibit the same propensity to undergo an EMT process, thereby determining whether they are able to acquire multi-resistance to various ALK–TKIs. We have also discovered the ability of silibinin to decrease the hypersecretion of the EMT-driver TGFβ, to directly block, to some extent, the activity of purified TGFβ receptors, and to attenuate the activation status of the SMAD pathway in response to ALK–TKIs. Since there exist bioavailable formulations of silibinin with proven clinical activity in oncology patients, our results suggest a new therapeutic strategy that would merit exploration to prevent or reverse resistance to ALK–TKIs induced by the EMT phenomenon