Reference Detail

Ref Type

Journal Article

PMID

(23039341)

Authors

Byron SA, Loch DC, Wellens CL, Wortmann A, Wu J, Wang J, Nomoto K, Pollock PM

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer	11		2012 Oct 05	75	Mol Cancer

URL

Abstract Text

Melanoma 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.The 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.Our 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
E6201	E6201	20	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
E6201			FLT3 Inhibitor 69 MEK1 Inhibitor 26	E6201 is a dual inhibitor of MEK1 and FLT3, which may lead to decreased tumor cell growth (Blood Nov 2013, 122 (21) 2683; PMID: 23039341, PMID: 29867224, PMID: 30264293).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF mutant	melanoma	sensitive	E6201 + LY294002	Preclinical	Actionable	In a preclinical study, E6201 and LY294002 synergistically inhibited proliferation of melanoma cell lines harboring BRAF mutations in culture, regardless of PTEN mutation status (PMID: 23039341).	23039341
HRAS wild-type	melanoma	sensitive	E6201	Preclinical	Actionable	In a preclinical study, E6201 inhibited proliferation of several melanoma cell lines in culture and hypersensitivity was associated with wild-type HRAS (PMID: 23039341).	23039341
BRAF mut PTEN mut	melanoma	decreased response	E6201	Preclinical - Cell line xenograft	Actionable	In a preclinical study, E6201 resulted in a cytostatic response in melanoma cell lines harboring both BRAF and PTEN mutations in culture and only inhibited tumor growth at very high doses in cell line xenograft models (PMID: 23039341).	23039341
PTEN wild-type	melanoma	sensitive	E6201	Preclinical	Actionable	In a preclinical study, E6201 inhibited proliferation of several melanoma cell lines in culture and sensitivity was associated with wild-type PTEN (PMID: 23039341).	23039341
NRAS wild-type	melanoma	sensitive	E6201	Preclinical	Actionable	In a preclinical study, E6201 inhibited proliferation of several melanoma cell lines in culture and hypersensitivity was associated with wild-type NRAS (PMID: 23039341).	23039341
BRAF mut PTEN wild-type	melanoma	sensitive	E6201	Preclinical - Cell line xenograft	Actionable	In a preclinical study, E6201 resulted in a cytocidal response in PTEN wild-type melanoma cell lines harboring BRAF mutations in culture and inhibited tumor growth in cell line xenograft models (PMID: 23039341).	23039341
BRAF mutant	melanoma	sensitive	E6201	Preclinical	Actionable	In a preclinical study, E6201 inhibited proliferation of several melanoma cell lines in culture and hypersensitivity was associated with BRAF mutations (PMID: 23039341).	23039341