![]() L’hétérogénéité intra-tumorale et la plasticité des cellules de mélanomes participent à la résistance thérapeutique. Malgré les thérapies actuelles (thérapies ciblant la voie BRAF/MEK et immunothérapies), de nombreux patients sont encore en échec thérapeutique à cause de l’émergence rapide de résistances. Le mélanome est le cancer cutané le plus agressif à cause de son importante hétérogénéité, son fort potentiel métastatique et sa résistance thérapeutique. While it is generally assumed that a higher dose is not critical, we found experimentally that a high physiological dabrafenib concentration fails to induce cell death in embedded 451LU melanoma spheroids. The prediction suggests an eight-fold increase in the steady-state concentration of potent desmethyl-dabrafenib and its inactive precursor carboxy-dabrafenib within four weeks upon 150 mg b.d. ![]() The MCPK model is qualitatively based on in vitro and quantitatively on clinical data to describe occupancy-dependent CYP3A4 enzyme induction, accumulation, and drug–drug interaction mechanisms. To clarify whether such elevated drug concentrations could be reached by long-term drug accumulation, we mechanistically coupled the pharmacokinetics (MCPK) of dabrafenib and its metabolites. A clinical drug-dose determination study shows increased pERK levels upon daily administration of more than 300 mg dabrafenib. However, dabrafenib monotherapy is associated with pERK reactivation, drug resistance, and consequential relapse. Altogether, our findings propose AXLi as a promising treatment in combination with standard therapy to improve therapeutic outcome in metastatic melanoma.ĭabrafenib inhibits the cell proliferation of metastatic melanoma with the oncogenic BRAF(V600)-mutation. When searching for mechanistic insights, AXLi was found to potentiate BRAFi-induced apoptosis, stimulate ferroptosis and inhibit autophagy. 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 treated ex vivo, the largest reduction in cell viability was observed when the two drugs were combined. Firstly, AXL was shown to be expressed in majority of melanoma lymph node metastases. 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. 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. More than half of metastatic melanoma patients receiving standard therapy fail to achieve a long-term survival due to primary and/or acquired resistance. Proteins are ranked based on fold-enrichment, with the most enriched at the. A heatmap from the RPPA analysis that shows significantly enriched (at least by 20%) proteins in the melanoma cells from the co-cultures versus the mono-cultures (n=3). Insert: MITF and AXL expression changes were confirmed by Western blotting (histone 3 (H3) as a loading control). The expression level in the co- cultures was normalized to the level in the mono-cultures set to 1. Relative gene expression of differentiation and mesenchymal signature genes, detected by q-PCR (average ± SEM, n=3) *, p < 0.05. To note, S6 phosphorylation at positions S235/236 (that can be regulated by MAPK in addition to mTOR) and S240/244. However, the phosphorylation of an AKT substrate, GSK-3β, and particularly an mTOR substrate, S6, as well as mTOR itself was significantly reduced by BRAFi in the mono- cultures but not in the co-cultures with fibroblasts ( Figure 6A, 6B and Supplementary Figure S3A-C). We observed only minor alterations in pAKT levels. compare levels of PI3K/AKT/mTOR-associated proteins in the mono-cultures and the co-cultures, phosphorylated AKT, GSK-3β, S6 and mTOR were analyzed in FACS-separated melanoma cells by Western blotting and/or Simple Western immunoassay.
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