miR‐200c/Bmi1 axis and epithelial–mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment

Abstract

Summary: Resistance to BRAF inhibitors ( BRAF i) is one of the major challenges for targeted therapies for BRAF ‐mutant melanomas. However, little is known about the role of micro RNA s in conferring BRAF i resistance. Herein, we demonstrate that miR‐200c expression is significantly reduced whereas miR‐200c target genes including Bmi1, Zeb2, Tubb3, ABCG 5, and MDR 1 are significantly increased in melanomas that acquired BRAF i resistance compared to pretreatment tumor biopsies. Similar changes were observed in BRAF i‐resistant melanoma cell lines. Overexpression of miR‐200c or knock‐down of Bmi1 in resistant melanoma cells restores their sensitivities to BRAF i, leading to deactivation of the PI 3K/ AKT and MAPK signaling cascades, and acquisition of epithelial–mesenchymal transition‐like phenotypes, including upregulation of E‐cadherin, downregulation of N‐cadherin, and ABCG 5 and MDR 1 expression. Conversely, knock‐down of miR‐200c or overexpression of Bmi1 in BRAF i‐sensitive melanoma cells activates the PI 3K/ AKT and MAPK pathways, upregulates N‐cadherin, ABCG 5, and MDR 1 expression, and downregulates E‐cadherin expression, leading to BRAF i resistance. Together, our data identify miR‐200c as a critical signaling node in BRAF i‐resistant melanomas impacting the MAPK and PI 3K/ AKT pathways, suggesting miR‐200c as a potential therapeutic target for overcoming acquired BRAF i resistance.