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MIG6 loss confers resistance to ALK/ROS1 inhibitors in NSCLC through EGFR activation by low-dose EGF
Nobuyuki Kondo1,2, Takahiro Utsumi1,3, Yuki Shimizu1,4
1Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan.
Abstract:
Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1-positive (ROS1+) 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+ 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 candidate genes. Among them, this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly, MIG6 loss induced 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 verified that MIG6 loss induces resistance to ROS1-TKIs in ROS1+ cell lines. This study found a potentially novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.
Insights
Acquired resistance to anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer can be overcome. Loss of MIG6 activates the EGFR pathway, leading to TKI resistance, which combination therapy can reverse.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tyrosine kinase inhibitor (TKI) therapy is effective for anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1-positive (ROS1+) non-small cell lung cancer (NSCLC).
- Acquired resistance to ALK and ROS1 TKIs is a significant clinical challenge in NSCLC patients.
- Understanding the molecular mechanisms of acquired resistance is crucial for developing effective treatment strategies.
Purpose of the Study:
- To identify genetic factors contributing to acquired resistance to ALK-TKIs in ALK+ NSCLC.
- To investigate the role of ERRFI1 (MIG6) in mediating resistance to ALK and ROS1 TKIs.
- To explore therapeutic strategies to overcome acquired TKI resistance in NSCLC.
Main Methods:
- Genome-wide CRISPR/Cas9 knockout screening was performed on an ALK+ NSCLC cell line.
- Sequencing analysis identified candidate genes involved in TKI resistance.
- In vitro and in vivo models were used to evaluate the efficacy of combination therapy.
Main Results:
- Loss of MIG6 (ERRFI1) was identified as a key factor inducing resistance to ALK-TKIs.
- MIG6 loss upregulates MAPK and PI3K/AKT/mTOR pathways via EGFR signaling activation by low-dose EGF.
- Combination therapy with ALK-TKIs and anti-EGFR antibodies effectively overcame acquired resistance in both ALK+ and ROS1+ NSCLC models.
Conclusions:
- MIG6 loss is a novel mechanism conferring resistance to ALK and ROS1 TKIs in NSCLC.
- EGFR pathway activation by low-dose ligands plays a critical role in acquired TKI resistance.
- Combination therapy targeting both ALK/ROS1 and EGFR pathways represents a promising strategy to overcome TKI resistance in NSCLC.
