Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells.
FEBS J
; 286(7): 1305-1318, 2019 04.
Article
in En
| MEDLINE
| ID: mdl-30719834
ABSTRACT
Cetuximab (CTX), a monoclonal antibody against epidermal growth factor receptor, is being widely used for colorectal cancer (CRC) with wild-type (WT) KRAS. However, its responsiveness is still very limited and WT KRAS is not enough to indicate such responsiveness. Here, by analyzing the gene expression data of CRC patients treated with CTX monotherapy, we have identified DUSP4, ETV5, GNB5, NT5E, and PHLDA1 as potential targets to overcome CTX resistance. We found that knockdown of any of these five genes can increase CTX sensitivity in KRAS WT cells. Interestingly, we further found that GNB5 knockdown can increase CTX sensitivity even for KRAS mutant cells. We unraveled that GNB5 overexpression contributes to CTX resistance by modulating the Akt signaling pathway from experiments and mathematical simulation. Overall, these results indicate that GNB5 might be a promising target for combination therapy with CTX irrespective of KRAS mutation.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Biomarkers, Tumor
/
Drug Resistance, Neoplasm
/
GTP-Binding Protein beta Subunits
/
Cetuximab
/
Antineoplastic Agents, Immunological
/
Models, Theoretical
/
Mutation
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
FEBS J
Journal subject:
BIOQUIMICA
Year:
2019
Document type:
Article