- J Invest Dermatol. 2009 Jun;129(6):1500-15. Epub 2008 Dec 11.
Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide.
Sinnberg T, Lasithiotakis K, Niessner H, Schittek B, Flaherty KT, Kulms D, Maczey E, Campos M, Gogel J, Garbe C, Meier F.
Division of Dermatologic Oncology, Department of Dermatology, University of Tuebingen, Tuebingen, Germany.
melanoma, the PI3K-AKT-mTOR (AKT) and RAF-MEK-ERK (MAPK) signaling
pathways are constitutively activated and appear to play a role in
chemoresistance. Herein, we investigated the effects of pharmacological
AKT and MAPK pathway inhibitors on chemosensitivity of melanoma cells
to cisplatin and temozolomide. Chemosensitivity was tested by examining
effects on growth, cell cycle, survival, expression of antiapoptotic
proteins, and invasive tumor growth of melanoma cells in monolayer and
organotypic culture, respectively. MAPK pathway inhibitors did not
significantly increase chemosensitivity. AKT pathway inhibitors
consistently enhanced chemosensitivity yielding an absolute increase of
cell growth inhibition up to 60% (P<0.05, combination therapy vs
monotherapy with inhibitors or chemotherapeutics). Cotreatment of
melanoma cells with AKT pathway inhibitors and chemotherapeutics led to
a 2- to 3-fold increase of apoptosis (P<0.05, combination therapy vs
monotherapy) and completely suppressed invasive tumor growth in
organotypic culture. These effects were associated with suppression of
the antiapoptotic Bcl-2 family protein Mcl-1. These data suggest that
inhibition of the PI3K-AKT-mTOR pathway potently increases sensitivity
of melanoma cells to chemotherapy.