[HTML][HTML] Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma
DJL Wong, L Robert, MS Atefi, A Lassen, G Avarappatt… - Molecular cancer, 2014 - Springer
DJL Wong, L Robert, MS Atefi, A Lassen, G Avarappatt, M Cerniglia, E Avramis, J Tsoi…
Molecular cancer, 2014•SpringerBackground In melanoma, dysregulation of the MAPK pathway, usually via BRAF V600 or
NRAS Q61 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 BRAF V600, NRAS mutant, or wild-type melanoma. Methods
The 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 …
NRAS Q61 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 BRAF V600, NRAS mutant, or wild-type melanoma. Methods
The 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 …
Background
In melanoma, dysregulation of the MAPK pathway, usually via BRAF V600 or NRAS Q61 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 BRAF V600 , NRAS mutant, or wild-type melanoma.
Methods
The 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.
Results
Sensitivity 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 BRAF V600 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.
Conclusions
Combining 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.
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