Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells

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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.
Publisher
WILEY
Issue Date
2019-04
Language
English
Article Type
Article
Citation

FEBS JOURNAL, v.286, no.7, pp.1305 - 1318

ISSN
1742-464X
DOI
10.1111/febs.14773
URI
http://hdl.handle.net/10203/262428
Appears in Collection
BiS-Journal Papers(저널논문)
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