Laboratory for Systems Biology and Bio-inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
FEBS J. 2019 Apr;286(7):1305-1318. doi: 10.1111/febs.14773. Epub 2019 Feb 20.
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.
西妥昔单抗（CTX）是一种针对表皮生长因子受体的单克隆抗体，广泛用于野生型（WT）KRAS 的结直肠癌（CRC）。然而，其反应性仍然非常有限，WT KRAS 不足以表明这种反应性。在这里，通过分析接受 CTX 单药治疗的 CRC 患者的基因表达数据，我们鉴定出 DUSP4、ETV5、GNB5、NT5E 和 PHLDA1 作为克服 CTX 耐药性的潜在靶点。我们发现敲低这五个基因中的任何一个都可以增加 KRAS WT 细胞对 CTX 的敏感性。有趣的是，我们进一步发现 GNB5 敲低甚至可以增加 KRAS 突变细胞对 CTX 的敏感性。我们通过实验和数学模拟揭示了 GNB5 过表达通过调节 Akt 信号通路导致 CTX 耐药。总的来说，这些结果表明，GNB5 可能是与 CTX 联合治疗的有前途的靶点，与 KRAS 突变无关。
