Therapeutics Targeting Mutant KRAS.
Annu Rev Med
; 72: 349-364, 2021 01 27.
Article
em En
| MEDLINE
| ID: mdl-33138715
ABSTRACT
Aberrations in rat sarcoma (RAS) viral oncogene are the most prevalent and best-known genetic alterations identified in human cancers. Indeed, RAS drives tumorigenesis as one of the downstream effectors of EGFR activation, regulating cellular switches and functions and triggering intracellular signaling cascades such as the MAPK and PI3K pathways. Of the three RAS isoforms expressed in human cells, all of which were linked to tumorigenesis more than three decades ago, KRAS is the most frequently mutated. In particular, point mutations in KRAS codon 12 are present in up to 80% of KRAS-mutant malignancies. Unfortunately, there are no approved KRAS-targeted agents, despite decades of research and development. Recently, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for renewed drug development efforts, specifically against KRASG12C. These inhibitors, such as AMG 510 and MRTX849, show promise in early-phase studies. Nevertheless, combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acetonitrilas
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Piperazinas
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Piridinas
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Pirimidinas
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DNA de Neoplasias
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Transformação Celular Neoplásica
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Proteínas Proto-Oncogênicas p21(ras)
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Mutação
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Neoplasias
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article