Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kawasaki, Japan.
PLoS One. 2020 Mar 4;15(3):e0229712. doi: 10.1371/journal.pone.0229712. eCollection 2020.
In non-small cell lung cancer (NSCLC), oncogenic driver mutations including those in KRAS and EGFR are typically mutually exclusive. However, recent reports indicate that multiple driver mutations are found in a certain percentage of cancers, and that the therapeutic responses of such cases with co-mutations of driver genes are largely unclear. Here, using CRISPR-Cas9-mediated genome editing, we generated isogenic cell lines harboring one or two copies of an EGFR-activating mutation from the human NSCLC cell line A549, which is known to harbor a homozygous KRAS gene mutation. In comparison with parent cells with KRAS mutation alone, cells with concomitant EGFR mutation exhibited higher sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) but not to conventional anti-cancer drugs. In particular, cells with two copies of EGFR mutation were markedly more sensitive to EGFR-TKIs compared with parent cells. Thus, the presence of concomitant EGFR mutation can affect the TKI response of KRAS-mutated cells, implying that EGFR-TKI may represent an effective treatment option against NSCLC with EGFR/KRAS co-mutation.
在非小细胞肺癌（NSCLC）中，致癌驱动基因突变，包括 KRAS 和 EGFR 的基因突变通常是相互排斥的。然而，最近的报告表明，一定比例的癌症中存在多种驱动基因突变，并且这些具有驱动基因突变共突变的病例的治疗反应在很大程度上尚不清楚。在这里，我们使用 CRISPR-Cas9 介导的基因组编辑，从已知携带纯合 KRAS 基因突变的人 NSCLC 细胞系 A549 中生成了携带一个或两个 EGFR 激活突变的同基因细胞系。与仅携带 KRAS 突变的亲本细胞相比，同时携带 EGFR 突变的细胞对 EGFR-酪氨酸激酶抑制剂（TKI）更敏感，但对传统抗癌药物不敏感。特别是，具有两个 EGFR 突变拷贝的细胞对 EGFR-TKI 的敏感性明显高于亲本细胞。因此，同时存在 EGFR 突变会影响 KRAS 突变细胞对 TKI 的反应，这意味着 EGFR-TKI 可能代表针对具有 EGFR/KRAS 共突变的 NSCLC 的有效治疗选择。
