Department of Nanobiomedical Science, Dankook University, Cheonan, Republic of Korea.
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
Int J Cancer. 2020 Apr 15;146(8):2194-2200. doi: 10.1002/ijc.32499. Epub 2019 Jul 9.
Somatic mutations of epidermal growth factor receptor (EGFR) occur in ~3% of colorectal cancer (CRC) patients. Here, through systematic functional screening of 21 recurrent EGFR mutations selected from public data sets, we show that 11 colon cancer-derived EGFR mutants (G63R, E114K, R165Q, R222C, S492R, P596L, K708R, E709K, G719S, G724S and L858R) are oncogenic and able to transform cells in a ligand-independent manner. We demonstrate that cellular transformation by these mutants requires receptor dimerization. Importantly, the EGF-induced and constitutive oncogenic potential of these EGFR mutants are inhibited by cetuximab or panitumumab in vivo and in vitro. Taken together, we propose that a subset of EGFR mutations can serve as genomic predictors for response to anti-EGFR antibodies and that metastatic CRC patients with such mutations may benefit from these drugs as part of the first-line therapy.
表皮生长因子受体 (EGFR) 的体细胞突变发生在约 3%的结直肠癌 (CRC) 患者中。在这里，我们通过对从公共数据集选择的 21 个反复出现的 EGFR 突变进行系统的功能筛选，表明 11 种结肠癌衍生的 EGFR 突变体（G63R、E114K、R165Q、R222C、S492R、P596L、K708R、E709K、G719S、G724S 和 L858R）是致癌的，能够以非配体依赖的方式转化细胞。我们证明，这些突变体的细胞转化需要受体二聚化。重要的是，EGF 诱导和这些 EGFR 突变体的组成性致癌潜能在体内和体外均可被西妥昔单抗或帕尼单抗抑制。综上所述，我们提出，一部分 EGFR 突变可作为抗 EGFR 抗体反应的基因组预测因子，具有此类突变的转移性 CRC 患者可能受益于这些药物作为一线治疗的一部分。
