Advertisement

ResearchIn-Press PreviewOncology Open Access | 10.1172/jci.insight.173688

MIG6 loss confers resistance to ALK/ROS1 inhibitors in NSCLC through EGFR activation by low-dose EGF

Nobuyuki Kondo,1 Takahiro Utsumi,1 Yuki Shimizu,1 Ai Takemoto,1 Tomoko Oh-hara,1 Ken Uchibori,2 Sophia Subat-Motoshi,3 Hironori Ninomiya,3 Kengo Takeuchi,4 Makoto Nishio,2 Yasunari Miyazaki,5 and Ryohei Katayama1

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Kondo, N. in: JCI | PubMed | Google Scholar

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Utsumi, T. in: JCI | PubMed | Google Scholar

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Shimizu, Y. in: JCI | PubMed | Google Scholar

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Takemoto, A. in: JCI | PubMed | Google Scholar

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Oh-hara, T. in: JCI | PubMed | Google Scholar

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Uchibori, K. in: JCI | PubMed | Google Scholar |

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Subat-Motoshi, S. in: JCI | PubMed | Google Scholar

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Ninomiya, H. in: JCI | PubMed | Google Scholar

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Takeuchi, K. in: JCI | PubMed | Google Scholar |

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Nishio, M. in: JCI | PubMed | Google Scholar |

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Miyazaki, Y. in: JCI | PubMed | Google Scholar |

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2Department of Thoracic Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Pathology, Japanese Foundation for Cancer Research, Tokyo, Japan

4Japanese Foundation for Cancer Research, Tokyo, Japan

5Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Find articles by Katayama, R. in: JCI | PubMed | Google Scholar |

Published November 2, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.173688.
Copyright © 2023, Kondo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 2, 2023 - Version history
View PDF
Abstract

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.

Graphical Abstract
graphical abstract
Supplemental material

View Uncropped blot

View

Version history
  • Version 1 (November 2, 2023): In-Press Preview
Advertisement
Advertisement