Intermittent Versus Continuous Dosing of MAPK Inhibitors in the Treatment of BRAF-Mutated Melanoma.

Publication date: Dec 21, 2019

The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi +/- MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated. An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules. In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both.

Reger de Moura, C., Vercellino, L., Jouenne, F., Baroudjian, B., Sadoux, A., Louveau, B., Delyon, J., Serror, K., Goldwirt, L., Merlet, P., Bouquet, F., Battistella, M., Lebb’e, C., and Mourah, S. Intermittent Versus Continuous Dosing of MAPK Inhibitors in the Treatment of BRAF-Mutated Melanoma. 25238. 2019 Transl Oncol (13):2.

Concepts Keywords
Apoptotic Melanoma treatment
Biomarker Equal tumor
Biomarkers Medicine
BRAF Clinical medicine
BRAF Inhibitor Biomarkers
MAPK Cancer
MEK Melanoma
Melanoma RTT
Modulations MEK inhibitor
Monotherapy BRAF
Pharmacodynamic
Tumor
Versus
Vivo
Xenografts

Semantics

Type Source Name
disease MESH Melanoma
pathway KEGG Melanoma
disease MESH development
drug DRUGBANK Pralatrexate
drug DRUGBANK Aspartame
disease MESH tumor
pathway KEGG Cell cycle

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