1. ¹Division of Dermatologic Oncology, Department of Dermatology, University of Tuebingen, Tuebingen, Germany
2. ²Abramson Cancer Center of the University of Pennsylvania, Philadelphia, USA
3. ³Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
4. ⁴Servicio de Dermatologia, Hospital General Universitario Gregorio Maranon, Madrid, Spain

Correspondence: Dr Friedegund Meier, Division of Dermatologic Oncology, Department of Dermatology, University of Tuebingen, Liebermeisterstr. 25, D-72076 Tübingen, Germany. E-mail: friedegund.meier@med.uni-tuebingen.de

⁵These authors contributed equally to this work

Received 18 December 2007; Revised 21 August 2008; Accepted 8 October 2008; Published online 11 December 2008.

Abstract

In 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.