Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases

Cancer Medicine

Heike Niessner⁶  Andrea Forschner⁶  Bernhard Klumpp⁷  Jürgen B. Honegger¹  Maria Witte¹¹  Antje Bornemann¹³  Reinhard Dummer¹⁰  Annemarie Adam⁹  Jürgen Bauer⁶  Ghazaleh Tabatabai⁸  Keith Flaherty²  Tobias Sinnberg⁶  Daniela Beck⁶  Ulrike Leiter⁶  Cornelia Mauch^4,6  Alexander Roesch^5,6  Benjamin Weide⁶  Thomas Eigentler⁶  Dirk Schadendorf^3,6  Claus Garbe⁶  Dagmar Kulms^6,12  Leticia Quintanilla-Martinez⁹ 

[1] Department of Neurosurgery, University of Tuebingen, Germany;Massachusetts General Hospital Cancer Center, Boston, Massachusetts;Department of Dermatology, University of Essen, Germany;Department of Dermatology, University of Cologne, Germany;Department of Dermatology, University of Homburg, Germany;Division of Dermatologic Oncology, Department of Dermatology, University of Tuebingen, Germany;Department of Diagnostic and Interventional Radiology, University of Tuebingen, Germany;Department of Neurology, University Hospital Zurich, Zurich, Switzerland;Institute of Pathology, University of Tuebingen, Germany;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland;Department of Surgery, University of Tuebingen, Germany;Department of Dermatology, University of Dresden, Germany;Department of Neuropathology, University of Tuebingen, Germany

关键词: AKT;    BRAF inhibitors;    brain metastasis;    melanoma;    therapy resistance;   

DOI  :  10.1002/cam4.50

来源: Wiley

【 摘 要 】

Abstract

Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance. The BRAF inhibitor vemurafenib significantly improved overall survival. However, brain metastases still limit the effectiveness of this therapy. In a series of patients, we observed that treatment with vemurafenib resulted in substantial regression of extracerebral metastases, but brain metastases developed. This study aimed to identify factors that contribute to treatment resistance in brain metastases. Matched brain and extracerebral metastases from melanoma patients had identical ERK, p-ERK, and AKT immunohistochemistry staining patterns, but there was hyperactivation of AKT (p-AKT) and loss of PTEN expression in the brain metastases. Mutation analysis revealed no differences in BRAF, NRAS, or KIT mutation status in matched brain and extracerebral metastases. In contrast, AKT, p-AKT, and PTEN expression was identical in monolayer cultures derived from melanoma brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness than melanoma cells stimulated by fibroblast-conditioned medium. Inhibition of PI3K-AKT signaling resensitized melanoma cells isolated from a vemurafenib-resistant brain metastasis to vemurafenib. Brain-derived factors appear to induce hyperactivation of the AKT survival pathway and to promote the survival and drug resistance of melanoma cells in the brain. Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.

【 授权许可】

CC BY   
© 2012 The Authors. Cancer Medicine published by Blackwell Publishing Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.