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Ref Type Journal Article
PMID (35332208)
Authors Nyakas M, Fleten KG, Haugen MH, Engedal N, Sveen C, Farstad IN, Flørenes VA, Prasmickaite L, Mælandsmo GM, Seip K
Title AXL inhibition improves BRAF-targeted treatment in melanoma.
Journal Scientific reports
Vol 12
Issue 1
Date 2022 Mar 24
URL
Abstract Text 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 AXLhigh molecular profile in melanoma, has been recently linked to such event, limiting treatment efficacy. 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 benefit of adding AXLi to the BRAF-targeted therapy was observed in pre-clinical AXLhigh melanoma models in vitro and in vivo. When searching for mechanistic insights, AXLi was found to potentiate BRAFi-induced apoptosis, stimulate ferroptosis and inhibit autophagy. Altogether, our findings propose AXLi as a promising treatment in combination with standard therapy to improve therapeutic outcome in metastatic melanoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
AXL over exp BRAF V600E melanoma sensitive Bemcentinib + Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, Bemcentinib (BGB-324) and Zelboraf (vemurafenib) combination treatment synergistically inhibited viability of melanoma cell lines harboring BRAF V600E and overexpressing Axl in culture, and resulted in improved tumor growth inhibition and tumor regression over either agent alone in a cell line xenograft model (PMID: 35332208). 35332208
AXL over exp melanoma sensitive Bemcentinib Preclinical - Cell culture Actionable In a preclinical study, Bemcentinib (BGB-324) treatment inhibited viability of a BRAF wild-type melanoma cell line overexpressing Axl in culture (PMID: 35332208). 35332208