Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

Molecular Cancer

Research

Sara A Byron¹  Candice L Wellens¹  Pamela M Pollock²  Jiayi Wu³  Kenichi Nomoto³  John Wang⁴  Andreas Wortmann⁵  David C Loch⁵ 

[1] Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA;Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA;Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, 4059, Kelvin Grove, Queensland, Australia;Eisai Inc., Andover, MA, USA;H3 Biomedicine Inc., Cambridge, MA, USA;Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, 4059, Kelvin Grove, Queensland, Australia;

关键词: Melanoma;    BRAF;    PTEN;    MEK inhibition;    E6201;    PI3K;    MAPK;   

DOI  :  10.1186/1476-4598-11-75

 received in 2012-03-05, accepted in 2012-10-02,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundMelanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines.ResultsThe majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1.ConclusionsOur data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

【 授权许可】

Unknown   
© Byron et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.