Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	22	3	2023 Mar 02	317-332	Mol Cancer Ther

URL

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	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 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 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	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
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	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 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 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 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 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	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 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 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