KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.
Cell
; 168(5): 817-829.e15, 2017 02 23.
Article
em En
| MEDLINE
| ID: mdl-28215705
ABSTRACT
Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzamidas
/
Neoplasias Colorretais
/
Proteínas Proto-Oncogênicas p21(ras)
/
Sistema de Sinalização das MAP Quinases
/
Difenilamina
/
Antineoplásicos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos