AXL inhibition improves BRAF-targeted treatment in melanoma

Abstract

More than half of metastatic melanoma patients receiving standard therapy fail to achieve a long-term survival due to primary and/or acquired resistance. Tumor cell ability to switch from epithelial to a more aggressive mesenchymal phenotype, attributed with AXL^high molecular profle in melanoma, has been recently linked to such event, limiting treatment efcacy. In the current study, we investigated the therapeutic potential of the AXL inhibitor (AXLi) BGB324 alone or in combination with the clinically relevant BRAF inhibitor (BRAFi) vemurafenib. Firstly, AXL was shown to be expressed in majority of melanoma lymph node metastases. When treated ex vivo, the largest reduction in cell viability was observed when the two drugs were combined. In addition, a therapeutic beneft of adding AXLi to the BRAF-targeted therapy was observed in pre-clinical AXL^high melanoma models in vitro and in vivo. When searching for mechanistic insights, AXLi was found to potentiate BRAFiinduced apoptosis, stimulate ferroptosis and inhibit autophagy. Altogether, our fndings propose AXLi as a promising treatment in combination with standard therapy to improve therapeutic outcome in metastatic melanoma.