Epithelial-to-mesenchymal transition is a mechanism of ALK inhibitor resistance in lung cancer independent of ALK mutation status

Mutations in the ALK gene are detectable in ~40% of ALK-rearranged lung cancers resistant to ALK inhibitors. While epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK-inhibitor resistance is largely unknown. In this study, we report that both ALK mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in an ALK-rearranged lung cancer patient. Digital PCR analyses combined with microdissection after immunohistochemical staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pre-treatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo. These findings indicate that HDAC inhibitor pre-treatment followed by a new ALK inhibitors may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor.

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