Reference Detail

Ref Type

Journal Article

PMID

(33273059)

Authors

Flemington V, Davies EJ, Robinson D, Sandin LC, Delpuech O, Zhang P, Hanson L, Farrington P, Bell S, Falenta K, Gibbons FD, Lindsay N, Smith A, Wilson J, Roberts K, Tonge M, Hopcroft P, Willis SE, Roudier MP, Rooney C, Coker EA, Jaaks P, Garnett MJ, Fawell SE, Jones CD, Ward RA, Simpson I, Cosulich SC, Pease JE, Smith PD

Title

AZD0364 Is a Potent and Selective ERK1/2 Inhibitor That Enhances Antitumor Activity in KRAS -Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	20	2	2021 Feb	238-249	Mol Cancer Ther

URL

Abstract Text

The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF -mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS -mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS -mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro , AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF -mutant and KRAS -mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF - and KRAS -mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS -mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS -mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS -mutant tumors.

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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
AZD0364	AZD0364	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZD0364		ATG-017\|ATG017\|ATG 017\|AZD-0364\|AZD 0364\|Tizaterkib	ERK Inhibitor (pan) 21 ERK1 Inhibitor 2 ERK2 Inhibitor 2	AZD0364 (ATG-017) is a selective ATP-competitive inhibitor of ERK1 and ERK2, which may promote apoptosis and tumor regression (PMID: 31710489, PMID: 33273059).

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	sensitive	AZD0364	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AZD0364 (ATG-017) inhibited cell growth, decreased phosphorylation of Erk target genes, and increased expression of apoptosis markers in melanoma cells harboring BRAF V600E in culture, and resulted in tumor regression in cell line xenograft models (PMID: 33273059).	33273059
BRAF V600E MAP2K1 Q56P NRAS Q61R	melanoma	sensitive	AZD0364	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AZD0364 (ATG-017) decreased phosphorylation of Erk target genes and increased expression of apoptosis markers in melanoma cells harboring BRAF V600E, MAP2K1 Q56P, and NRAS Q61R in culture, and inhibited tumor growth in cell line xenograft models (PMID: 33273059).	33273059