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.

Autor:	Flemington V; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom. vikki.flemington@astrazeneca.com., Davies EJ; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Robinson D; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Sandin LC; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Delpuech O; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Zhang P; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Hanson L; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Farrington P; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Bell S; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Falenta K; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Gibbons FD; DMPK, Oncology, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom and Waltham, Massachusetts., Lindsay N; DMPK, Oncology, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom and Waltham, Massachusetts., Smith A; DMPK, Oncology, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom and Waltham, Massachusetts., Wilson J; DMPK, Oncology, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom and Waltham, Massachusetts., Roberts K; Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, England, United Kingdom., Tonge M; Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, England, United Kingdom., Hopcroft P; Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, England, United Kingdom., Willis SE; Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Roudier MP; Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Rooney C; Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Coker EA; Wellcome Sanger Institute, Cambridge, England, United Kingdom., Jaaks P; Wellcome Sanger Institute, Cambridge, England, United Kingdom., Garnett MJ; Wellcome Sanger Institute, Cambridge, England, United Kingdom., Fawell SE; Oncology R&D, AstraZeneca, Waltham, England, United Kingdom., Jones CD; Former employee of AstraZeneca., Ward RA; Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom., Simpson I; Former employee of AstraZeneca., Cosulich SC; Oncology R&D, AstraZeneca, Waltham, England, United Kingdom., Pease JE; Oncology R&D, AstraZeneca, Waltham, England, United Kingdom., Smith PD; Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 Feb; Vol. 20 (2), pp. 238-249. Date of Electronic Publication: 2020 Dec 03.
DOI:	10.1158/1535-7163.MCT-20-0002
Abstrakt:	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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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