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|Ref Type||Journal Article|
|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.|
|Date||2022 Mar 24|
|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.|
|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|