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Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells
Author(s) -
Park SangMin,
Hwang Chae Young,
Cho SungHwan,
Lee Daewon,
Gong JeongRyeol,
Lee Soobeom,
Nam Sohee,
Cho KwangHyun
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14773
Subject(s) - kras , cetuximab , gene knockdown , colorectal cancer , epidermal growth factor receptor , cancer research , mutant , mutation , biology , gene , cancer , genetics
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 DUSP 4, ETV 5, GNB 5, NT 5E, and PHLDA 1 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 GNB 5 knockdown can increase CTX sensitivity even for KRAS mutant cells. We unraveled that GNB 5 overexpression contributes to CTX resistance by modulating the Akt signaling pathway from experiments and mathematical simulation. Overall, these results indicate that GNB 5 might be a promising target for combination therapy with CTX irrespective of KRAS mutation.