Abstract
8526 Background: Brain metastases are a major contributor to mortality in stage IV melanoma patients. In melanoma, the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways play a major role in tumor progression and therapy resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib recently gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, ongoing clinical studies suggest short-lived responses to BRAF inhibitors in melanoma brain metastases. Methods: We observed in several melanoma patients that chemotherapeutics or BRAF inhibitors yielded a significant regression of extracerebral metastases while brain metastases progressed or newly occurred. We therefore aimed at identifying factors that may contribute to treatment resistance of brain metastases. Results: Immunohistochemistry of matched brain and extracerebral melanoma metastases demonstrated an identical pattern of ERK, p-ERK and AKT staining but a different pattern of p-AKT and PTEN staining with hyperactivation of AKT and loss of PTEN expression in brain metastases. Mutation analysis revealed no difference in BRAF, NRAS or KIT mutation status in matched brain and extracerebral metastases. By contrast, in monolayer culture expression of ERK, p-ERK, AKT, p-AKT and PTEN was identical in cell lines derived from brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed hyperactivation of AKT compared to melanoma cells stimulated by fibroblast-conditioned medium. When inhibiting the MAPK and AKT signaling pathways at different levels in cells freshly isolated from melanoma brain metastases, growth inhibition and apoptosis induction was most pronounced with novel PI3K inhibitors such as BKM120 and BEZ235. Conclusions: These data suggest that 1) hyperactivation of the AKT survival pathway is brain environment-induced and relevant for the survival of melanoma cells in the brain parenchyma and that 2) inhibition of AKT signaling may be a suitable strategy to enhance and/or prolong the antitumor effect of chemotherapeutics or BRAF inhibitors in melanoma brain metastases.
Highlights
The prognosis for melanoma patients with distant metastases is poor, with a median overall survival time of about 8 months [1], reflecting the failure of the chemotherapy and immunotherapy regimens that were used in the past
A recent phase III study showed that the BRAFV600E kinase inhibitor vemurafenib induced partial or complete tumor regression in 48% of patients with BRAFV600E-mutated metastatic melanoma as compared with 5% of patients treated with the classical chemotherapeutic agent dacarbazine [4]
Brain metastases occur in the majority of patients and are the most common cause of death
Summary
The prognosis for melanoma patients with distant metastases is poor, with a median overall survival time of about 8 months [1], reflecting the failure of the chemotherapy and immunotherapy regimens that were used in the past. The overall survival of melanoma patients with brain metastases is generally very poor, with a median survival time of 5 months [6]. Patients treated with neuro- or radiosurgery appear to have a longer median survival of about 9 months [6, 7] Chemotherapeutic agents such as temozolomide that are used for treating primary brain tumors are not effective for cerebral melanoma metastases [8]. Recent and ongoing clinical trials show clinical activity of BRAF inhibitors in patients with asymptomatic melanoma brain metastases [10, 11]. Effects of BRAF inhibitors in melanoma brain metastases appear to be limited
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