BACKGROUND: In melanoma, several signalling pathways are constitutively activated. Among them, the RAS/RAF/MEK/ERK (MAPK) and PI3K/AKT (AKT) signalling pathways are activated through multiple mechanisms and appear to play a major role in melanoma development and progression. OBJECTIVES: In this study, we examined whether targeting the MAPK and/or AKT signalling pathways would have therapeutic effects against melanoma. METHODS: Using a panel of pharmacological inhibitors (BAY 43-9006, PD98059, U0126, wortmannin, LY294002) we inhibited the MAPK and AKT signalling pathways at different levels and evaluated the effects on growth, survival and invasion of melanoma cells in monolayer and organotypic skin culture. RESULTS: Antiproliferative and proapoptotic effects of inhibitors alone in monolayer culture were disappointing and varied among the different cell lines. In contrast, combined targeting of the MAPK and AKT signalling pathways significantly inhibited growth and enhanced apoptosis in monolayer culture. To verify our data in a more physiological context we incorporated melanoma cells into regenerated human skin mimicking the microenvironment of human melanoma. Combinations of MAPK and AKT inhibitors completely suppressed invasive tumour growth of melanoma cells in regenerated human skin. CONCLUSIONS: Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.
BACKGROUND: In melanoma, several signalling pathways are constitutively activated. Among them, the RAS/RAF/MEK/ERK (MAPK) and PI3K/AKT (AKT) signalling pathways are activated through multiple mechanisms and appear to play a major role in melanoma development and progression. OBJECTIVES: In this study, we examined whether targeting the MAPK and/or AKT signalling pathways would have therapeutic effects against melanoma. METHODS: Using a panel of pharmacological inhibitors (BAY 43-9006, PD98059, U0126, wortmannin, LY294002) we inhibited the MAPK and AKT signalling pathways at different levels and evaluated the effects on growth, survival and invasion of melanoma cells in monolayer and organotypic skin culture. RESULTS: Antiproliferative and proapoptotic effects of inhibitors alone in monolayer culture were disappointing and varied among the different cell lines. In contrast, combined targeting of the MAPK and AKT signalling pathways significantly inhibited growth and enhanced apoptosis in monolayer culture. To verify our data in a more physiological context we incorporated melanoma cells into regenerated human skin mimicking the microenvironment of humanmelanoma. Combinations of MAPK and AKT inhibitors completely suppressed invasive tumour growth of melanoma cells in regenerated human skin. CONCLUSIONS: Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.
Authors: John T Lee; Ling Li; Patricia A Brafford; Marcia van den Eijnden; Molly B Halloran; Katrin Sproesser; Nikolas K Haass; Keiran S M Smalley; James Tsai; Gideon Bollag; Meenhard Herlyn Journal: Pigment Cell Melanoma Res Date: 2010-12 Impact factor: 4.693
Authors: Sabine Damm; Petra Koefinger; Martina Stefan; Christian Wels; Gabor Mehes; Erika Richtig; Helmut Kerl; Marcus Otte; Helmut Schaider Journal: J Invest Dermatol Date: 2010-04-01 Impact factor: 8.551
Authors: S Martín-Algarra; M T Fernández-Figueras; J A López-Martín; A Santos-Briz; A Arance; M D Lozano; A Berrocal; J J Ríos-Martín; E Espinosa; J L Rodríguez-Peralto Journal: Clin Transl Oncol Date: 2013-10-16 Impact factor: 3.405
Authors: Stuart J Gallagher; John F Thompson; James Indsto; Lyndee L Scurr; Margaret Lett; Bo-Fu Gao; Ruth Dunleavey; Graham J Mann; Richard F Kefford; Helen Rizos Journal: Neoplasia Date: 2008-11 Impact factor: 5.715
Authors: Peng Hou; Dingxie Liu; Meiju Ji; Zhi Liu; James M Engles; Richard L Wahl; Mingzhao Xing Journal: PLoS One Date: 2009-07-10 Impact factor: 3.240