Cooperative induction of receptor tyrosine kinases contributes to adaptive MAPK drug resistance in melanoma through the PI3K pathway

Abstract

emurafenib-induced drug resistance in melanoma has been linked to receptor tyrosinekinase (RTK) upregulation. The MITF and SOX10 genes play roles as master regulators ofmelanocyte and melanoma development. Here, we aimed to explore the complex mecha-nisms behind the MITF/SOX10-controlled RTK-induced drug resistance in melanoma. Toachieve this, we used a number of molecular techniques, including melanoma patient datafrom TCGA, vemurafenib-resistant melanoma cell lines, and knock-down studies. The mel-anoma cell lines were classified as proliferative or invasive based upon their MITF/AXLexpression activity. We measured the changeof expression activity for MITF/SOX10 andtheir receptor (AXL/ERBB3) and ligand (NRG1/GAS6) targets known to be involved inRTK-induced drug resistance after vemurafenib treatment. We find that melanoma celllines characterized as proliferative (high MITF low AXL), transform into an invasive (lowMITF, high AXL) cell state after vemurafenibresistance, indicating novel feedback loopsand advanced compensatory regulation mechanisms between the master regulators,receptors, and ligands involved in vemurafenib-induced resistance. Together, our data dis-close fine-tuned mechanisms involved in RTK-facilitated vemurafenibresistance that willbe challenging to overcome by using single drug targeting strategies against melanoma.