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: | Vikki Flemington, Elizabeth A. Coker, Patricia Jaaks, Linda Sandin, Philip Hopcroft, Nicola Lindsay, Aaron Smith, Lyndsey Hanson, David Robinson, Clifford David Jones, Mathew J. Garnett, Karen Roberts, Francis D. Gibbons, Stephen Fawell, Richard A. Ward, Sabina Cosulich, Iain Simpson, Emma J. Davies, Oona Delpuech, J. Elizabeth Pease, Paul D. Smith, Martine P. Roudier, Claire Rooney, Katarzyna Falenta, Joanne Wilson, Sophie E. Willis, Sigourney Bell, Paul Farrington, Michael Tonge, Pei Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research Chemistry Kinase MEK inhibitor Melanoma medicine.disease_cause medicine.disease digestive system diseases 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis Selumetinib medicine Cancer research KRAS Signal transduction Carcinogenesis neoplasms |
| Zdroj: | Molecular Cancer Therapeutics. 20:238-249 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-20-0002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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