Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer.
Nat Cancer
; 3(2): 219-231, 2022 02.
Article
en En
| MEDLINE
| ID: mdl-35145327
ABSTRACT
Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRASG12 mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
/
Quinasas de Proteína Quinasa Activadas por Mitógenos
Tipo de estudio:
Guideline
Límite:
Humans
Idioma:
En
Revista:
Nat Cancer
Año:
2022
Tipo del documento:
Article
País de afiliación:
Israel