尽管酪氨酸激酶抑制剂（TKI）治疗在间变性淋巴瘤激酶（ALK）和ROS原癌基因1（ROS1）阳性的非小细胞肺癌（NSCLC）患者中显示出显着的临床疗效，但大多数患者最终会复发反抗。因此，使用未经 ALK-TKI 治疗的胸腔积液建立的 ALK 阳性 NSCLC 细胞系进行全基因组 CRISPR-Cas9 敲除筛选。 ALK-TKI 治疗 9 天后，进行了测序分析，确定了多个肿瘤抑制基因，例如 NF2 或 MED12，以及多个新的候选基因。其中这项研究重点关注ERRFI1，它被称为MIG6，对EGFR信号传导负调节。有趣的是，MIG6 缺失通过相当低剂量的 EGF 治疗诱导了对 ALK-TKIs 的耐药性，该剂量相当于通过上调 MAPK 和 PI3K/Akt/mTOR 途径的血浆浓度。 ALK-TKI 和抗 EGFR 抗体的联合治疗可以克服体内和体外模型中的获得性耐药。此外，这证实了 MIG6 缺失会诱导 ROS1 阳性细胞系对 ROS1-TKI 产生耐药性。这项研究发现了一种新因子，通过用低剂量配体激活 EGFR 通路，在 ALK 和 ROS1-TKI 耐药中发挥作用。

Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1)-positive non-small cell lung cancer (NSCLC), most of these patients eventually relapse with acquired resistance. Therefore, genome-wide CRISPR-Cas9 knockout screening was performed using an ALK-positive NSCLC cell line established from pleural effusion without ALK-TKI treatment. After 9 days of ALK-TKI therapy, sequencing analysis was performed, which identified several tumor-suppressor genes, such as NF2 or MED12, and multiple new candidate genes. Among them this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly MIG6 loss induced the resistance to ALK-TKIs by treatment with quite a low dose of EGF, which is equivalent to plasma concentration through the upregulation of MAPK and PI3K/Akt/mTOR pathways. Combination therapy with ALK-TKIs and anti-EGFR antibodies could overcome the acquired resistance in both in vivo and in vitro models. In addition, this confirmed that MIG6 loss induces resistance to ROS1-TKIs in ROS1-positive cell lines. This study found a novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.