Abstract A292: Salinomycin, an anti-cancer stem cell antibiotic, overcomes acquired resistance to BRAF inhibitors in BRAF-mutant human melanoma cell lines.

Abstract

Abstract Advanced malignant melanoma is one of the most lethal cancers, because it is highly metastatic and refractory to conventional chemotherapy. About 60% of melanomas harbor oncogenic BRAF mutations which aberrantly activate MEK/ERK signaling pathway. BRAF and MEK inhibitors have been shown efficacious in patients with BRAF-mutant melanoma, but there is not effective target therapy for BRAF wild type melanomas. Unfortunately acquired resistance to BRAF targeted therapies is a common event: 50% of treated patients progressed within 6 to 7 months after the initiation of treatment. Resistance is associated with reactivation of the MAPK pathway (through development of de novo NRAS, NF1 or MEK mutations) or activation of parallel pathways, such as the PI3K/AKT pathway. Cancer stem cells (CSCs) represent a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity. It has been postulated that CSC could be linked to acquired resistance to both conventional and targeted therapies. Salinomycin, an ionophore antibiotic, has been shown to selectively kill CSCs in several types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway, and other CSC pathways. In this study, we have analyzed a wide panel of human melanoma cell lines with a known mutational status of BRAF, tumor suppressors, and other frequently mutated oncogenes in melanoma, and their sensibility to several protein kinase inhibitors (PKIs) in vitro, including the BRAF inhibitor vemurafenib. We have combined these PKIs with the CSC inhibitor, salinomycin, in order to find therapeutically relevant synergies. To better characterize CSC phenotype, we carried out tumorsphere formation assays in vitro, FACS analysis of CSC canonical markers, to find that salinomycin sensitizes BRAF-wild type melanoma cell lines to the cytotoxic effect of particular PKIs. Importantly, we demonstrated that salinomycin-PKI combination therapy supresses the emergence of vemurafenib-resistant subpopulations in BRAF-mutant melanoma cell lines. Overall, we find that targeting CSC property of wild-type BRAF inhibitor with salinomycin significantly potentiates therapeutic activity of PKIs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A292. Citation Format: Daniel Crespo, Ines Pulido, Maria L. Rodriguez, Salvador Aparisi, Alejandro Lopez, Margaret Soucheray, Fatima Al-Shahrour, Takeshi Shimamura, Angel Ortega, Julian Carretero. Salinomycin, an anti-cancer stem cell antibiotic, overcomes acquired resistance to BRAF inhibitors in BRAF-mutant human melanoma cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A292.