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.
Nobuyuki Kondo, Takahiro Utsumi, Yuki Shimizu, Ai Takemoto, Tomoko Oh-hara, Ken Uchibori, Sophia Subat-Motoshi, Hironori Ninomiya, Kengo Takeuchi, Makoto Nishio, Yasunari Miyazaki, Ryohei Katayama