KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.
Cell
; 168(5): 817-829.e15, 2017 02 23.
Article
en 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Benzamidas
/
Neoplasias Colorrectales
/
Proteínas Proto-Oncogénicas p21(ras)
/
Sistema de Señalización de MAP Quinasas
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Difenilamina
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Antineoplásicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos