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Ref Type Journal Article
PMID (36622773)
Authors Takano K, Munehira Y, Hatanaka M, Murakami R, Shibata Y, Shida T, Takeuchi K, Takechi S, Tabata T, Shimada T, Kishikawa S, Matsui Y, Ubukata O, Seki T, Kaneta Y
Title Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma.
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Abstract Text Patients with melanoma with activating BRAF mutations (BRAF V600E/K) initially respond to combination therapy of BRAF and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRAF gene and subsequent reactivation of the MAPK pathway. DS03090629 is a novel and orally available MEK inhibitor that inhibits MEK in an ATP-competitive manner. In both in vitro and in vivo settings, potent inhibition of MEK by DS03090629 or its combination with the BRAF inhibitor dabrafenib was demonstrated in a mutant BRAF-overexpressing melanoma cell line model that exhibited a higher MEK phosphorylation level than the parental cell line and then became resistant to dabrafenib and the MEK inhibitor trametinib. DS03090629 also exhibited superior efficacy against a melanoma cell line-expressing mutant MEK1 protein compared with dabrafenib and trametinib. Biophysical analysis revealed that DS03090629 retained its affinity for the MEK protein regardless of its phosphorylation status, whereas the affinity of trametinib declined when the MEK protein was phosphorylated. These results suggest that DS03090629 may be a novel therapeutic option for patients who acquire resistance to the current BRAF- and MEK-targeting therapies.

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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
DS03090629 DS03090629 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
DS03090629 DS-03090629|DS 03090629 MEK1 Inhibitor 26 MEK2 Inhibitor 24 DS03090629 inhibits Mek1/2, which potentially decreases tumor cell proliferation and tumor growth (PMID: 36622773).
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 V600E BRAF over exp melanoma predicted - sensitive DS03090629 Preclinical - Cell line xenograft Actionable In a preclinical study, DS03090629 inhibited Erk but not Mek phosphorylation and proliferation in a melanoma cell line overexpressing BRAF V600E in culture and led to tumor stasis in a cell line xenograft model (PMID: 36622773). 36622773
BRAF V600E melanoma sensitive Dabrafenib + DS03090629 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of DS03090629 and Tafinlar (dabrafenib) inhibited Erk phosphorylation and proliferation in a melanoma cell line harboring BRAF V600E in culture and induced tumor regression in a cell line xenograft model (PMID: 36622773). 36622773
BRAF V600E MAP2K1 F53L melanoma conflicting Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited Mek but not Erk phosphorylation and did not inhibit proliferation in a melanoma cell line harboring BRAF V600E and expressing MAP2K1 F53L in culture (PMID: 36622773). 36622773
BRAF V600E BRAF over exp melanoma sensitive Dabrafenib + DS03090629 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of DS03090629 and Tafinlar (dabrafenib) inhibited Erk phosphorylation and proliferation in a melanoma cell line overexpressing BRAF V600E in culture and induced tumor regression in a cell line xenograft model (PMID: 36622773). 36622773
BRAF V600E melanoma predicted - sensitive DS03090629 Preclinical - Cell line xenograft Actionable In a preclinical study, DS03090629 inhibited Erk and Mek phosphorylation and proliferation in a melanoma cell line harboring BRAF V600E in culture and led to tumor stasis in a cell line xenograft model (PMID: 36622773). 36622773
BRAF V600E MAP2K1 F53L melanoma resistant Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, Tafinlar (dabrafenib) inhibited Erk and Mek phosphorylation but did not inhibit proliferation in a melanoma cell line harboring BRAF V600E and expressing MAP2K1 F53L in culture (PMID: 36622773). 36622773
BRAF V600E NRAS Q61K melanoma resistant Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing NRAS Q61K was resistant to Tafinlar (dabrafenib) in culture (PMID: 36622773). 36622773
BRAF V600E NRAS Q61K melanoma resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing NRAS Q61K was resistant to Mekinist (trametinib) in culture (PMID: 36622773). 36622773
BRAF V600E BRAF over exp melanoma resistant Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line overexpressing BRAF V600E was resistant to Tafinlar (dabrafenib) in culture (PMID: 36622773). 36622773
BRAF V600E NRAS Q61K melanoma predicted - resistant DS03090629 Preclinical - Cell culture Actionable In a preclinical study, DS03090629 inhibited Erk but not Mek phosphorylation and did not inhibit proliferation in a melanoma cell line harboring BRAF V600E and expressing NRAS Q61K in culture (PMID: 36622773). 36622773
BRAF V600E BRAF over exp melanoma resistant Dabrafenib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line overexpressing BRAF V600E was resistant to the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) in culture (PMID: 36622773). 36622773
BRAF V600E MAP2K1 F53L melanoma sensitive DS03090629 Preclinical - Cell culture Actionable In a preclinical study, DS03090629 inhibited Erk and Mek phosphorylation and proliferation in a melanoma cell line harboring BRAF V600E and expressing MAP2K1 F53L in culture (PMID: 36622773). 36622773
BRAF V600E BRAF over exp melanoma resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line overexpressing BRAF V600E was resistant to Mekinist (trametinib) in culture (PMID: 36622773). 36622773