MIG6 Mediates Adaptive and Acquired Resistance to ALK/ROS1 Fusion Kinase Inhibition through EGFR Bypass Signaling.

Abstract

Despite the initial benefit from tyrosine kinase inhibitors (TKI) targeting oncogenic ALK and ROS1 gene fusions in non-small cell lung cancer, complete responses are rare and resistance ultimately emerges from residual tumor cells. Although several acquired resistance mechanisms have been reported at the time of disease progression, adaptative resistance mechanisms that contribute to residual diseases before the outgrowth of tumor cells with acquired resistance are less clear. For the patients who have progressed after TKI treatments, but do not demonstrate ALK/ROS1 kinase mutations, there is a lack of biomarkers to guide effective treatments. Herein, we found that phosphorylation of MIG6, encoded by the ERRFI1 gene, was downregulated by ALK/ROS1 inhibitors as were mRNA levels, thus potentiating EGFR activity to support cell survival as an adaptive resistance mechanism. MIG6 downregulation was sustained following chronic exposure to ALK/ROS1 inhibitors to support the establishment of acquired resistance. A higher ratio of EGFR to MIG6 expression was found in ALK TKI-treated and ALK TKI-resistant tumors and correlated with the poor responsiveness to ALK/ROS1 inhibition in patient-derived cell lines. Furthermore, we identified and validated a MIG6 EGFR-binding domain truncation mutation in mediating resistance to ROS1 inhibitors but sensitivity to EGFR inhibitors. A MIG6 deletion was also found in a patient after progressing to ROS1 inhibition. Collectively, this study identifies MIG6 as a novel regulator for EGFR-mediated adaptive and acquired resistance to ALK/ROS1 inhibitors and suggests EGFR to MIG6 ratios and MIG6-damaging alterations as biomarkers to predict responsiveness to ALK/ROS1 and EGFR inhibitors.

• Authors: Nan Chen, Logan C Tyler, Anh T Le, Eric A Welsh, Bin Fang, Andrew Elliott, Kurtis D Davies, Thomas Danhorn, Gregory J Riely, Marc Ladanyi, Eric B Haura, Robert C Doebele
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 23 Issue 1 Pg. 92-105 (Jan 03 2024) ISSN: 1538-8514 [Electronic] United States
• PMID: 37748191 (Publication Type: Journal Article)
• Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Anaplastic Lymphoma Kinase
• Protein-Tyrosine Kinases
• ErbB Receptors
• Proto-Oncogene Proteins
• Protein Kinase Inhibitors
• Biomarkers
• ROS1 protein, human
• EGFR protein, human

Topics

• Humans
• Anaplastic Lymphoma Kinase (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Protein-Tyrosine Kinases (genetics)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• ErbB Receptors
• Proto-Oncogene Proteins (genetics, pharmacology)
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Biomarkers
• Drug Resistance, Neoplasm (genetics)
• Cell Line, Tumor