Abstract 425: Targeting embryonic signaling pathways in melanoma

Abstract

Abstract Melanoma incidence is quickly rising and the average survival for a patient with metastatic disease is less than one year. Novel targeted therapies, such as B-Raf mutant kinase inhibitors, have shown dramatic initial responses, but resistance to single agent therapy inevitably ensues. We hypothesize that melanoma stem-like cells may be important in melanoma progression and may play a role in chemoresistance to targeted therapy. We have profiled melanoma cell lines as well as metastatic melanoma tissue for activation of embryonic stem cell pathways via microarray and quantitative RT-PCR. We observed upregulation of the Hedgehog pathway in a subset of cell lines and in human melanoma tissue and found that Smoothened (SMO) expression was associated with significantly shorter recurrence-free survival in metastatic melanoma patients. We also found that small molecule inhibition or genetic silencing of Smoothened (SMO) decreased melanoma cell proliferation and migration in vitro and identified overexpression of GLI2 as a marker of resistance to SMO inhibition. These findings suggest that inhibitors of hedgehog pathway signaling, already in clinical trials in other tumor types, may be a novel strategy for advanced melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 425. doi:1538-7445.AM2012-425