Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment.
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.


OBJECTIVE
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.
Meier
F
F
Division of Dermatological Oncology, Department of Dermatology, University of Tübingen, Tübingen, Germany. friedegund.meier@med.uni-tuebingen.de
Busch
S
S
Lasithiotakis
K
K
Kulms
D
D
Garbe
C
C
Maczey
E
E
Herlyn
M
M
Schittek
B
B
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D000077191:Wortmannin
D000730:Androstadienes; D001557:Benzenesulfonates; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D004121:Dimethyl Sulfoxide