title: Crosstalk signaling in targeted melanoma therapy.
abstract: Inhibition of the BRAF/MAPK pathway belongs to the standard therapies for patients with activating BRAFV600E/Kmutations. However, even in well-responding tumors, anti-tumorigenic effect and clinical benefit are only transient, and the original tumors often relapse. This demonstrates that there are remaining residual tumors, which have withstood therapy-induced apoptosis and which have the potential to resume growth. Although BRAF mutant melanoma cells seem to depend on BRAF/MAPK signaling, the inhibition of this pathway triggers several events, which modulate the tumor as well as the tumor niche. After a certain adaptation period, this can turn out to be beneficial for tumor growth and metastasis-even in cases of good initial tumor response. This review sheds light on the biology of BRAF/MEK inhibitor-sensitive melanoma cells, which survive targeted therapy and will address the crosstalk signaling events occurring in BRAF mutant melanomas when the BRAF/MAPK pathway is fully blocked. The knowledge of these events is important for potential future drug combinations, which enhance the inhibitory effect of BRAF/MEK inhibition, particularly in patients not eligible for immune therapy.
authors.affiliation: Department of Physiological Chemistry, Biocenter, University of Würzburg, Am Hubland, 97074, Würzburg, Germany. svenja.meierjohann@biozentrum.uni-wuerzburg.de.|Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany. svenja.meierjohann@biozentrum.uni-wuerzburg.de.
authors.forename: Svenja
authors.initials: S
authors.lastname: Meierjohann
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology*; D058990:Molecular Targeted Therapy; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D048493:Proto-Oncogene Proteins B-raf
keywords: EGFR; MITF; Melanoma therapy; Negative feedback; Tumor microenvironment; WNT