Abstract
BackgroundIn melanoma, dysregulation of the MAPK pathway, usually via BRAFV600 or NRASQ61 somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAFV600, NRAS mutant, or wild-type melanoma.MethodsThe 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined.ResultsSensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAFV600 mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis.ConclusionsCombining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-194) contains supplementary material, which is available to authorized users.
Highlights
In melanoma, dysregulation of the MAPK pathway, usually via BRAFV600 or NRASQ61 somatic mutations, leads to constitutive ERK signaling
MAPK-independent mechanisms of acquired resistance occur, through the upregulation of receptor tyrosine kinases (RTKs), such as the plateletderived growth factor beta (PDGFRβ) [6], or the insulin growth factor receptor 1 (IGF1R), or deletions of PTEN [12]. These all lead primarily to enhanced PI3K/AKT/ mTOR signaling rather than reactivation of the MAPK pathway. These mechanisms of acquired resistance are generally mutually exclusive and predict for susceptibility to inhibition with other targeted therapies in vitro; cell lines with secondary NRASQ61 mutations remain sensitive to a MEK inhibitor [13] (MEKi), while cell lines displaying Receptor tyrosine kinase (RTK) upregulation are cross-resistant to a MEKi but sensitive to a PI3K, AKT or mTOR inhibitor in combination with vemurafenib [14,15]
BRAF-mutant melanoma cell lines are sensitive to ERK inhibition Twenty-one melanoma cell lines containing mutations in the BRAF gene were evaluated to determine sensitivity to SCH772984 (ERKi)
Summary
Dysregulation of the MAPK pathway, usually via BRAFV600 or NRASQ61 somatic mutations, leads to constitutive ERK signaling. MAPK-independent mechanisms of acquired resistance occur, through the upregulation of receptor tyrosine kinases (RTKs), such as the plateletderived growth factor beta (PDGFRβ) [6], or the insulin growth factor receptor 1 (IGF1R), or deletions of PTEN [12] These all lead primarily to enhanced PI3K/AKT/ mTOR signaling rather than reactivation of the MAPK pathway. These mechanisms of acquired resistance are generally mutually exclusive and predict for susceptibility to inhibition with other targeted therapies in vitro; cell lines with secondary NRASQ61 mutations remain sensitive to a MEK inhibitor [13] (MEKi), while cell lines displaying RTK upregulation are cross-resistant to a MEKi but sensitive to a PI3K, AKT or mTOR inhibitor in combination with vemurafenib [14,15]
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