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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI150517

MERTK activation drives osimertinib resistance in EGFR-mutant non-small cell lung cancer

Dan Yan,1 Justus M. Huelse,1 Dmitri Kireev,2 Zikang Tan,1 Luxiao Chen,3 Subir Goyal,3 Xiaodong Wang,2 Stephen V. Frye,2 Madhusmita Behera,3 Frank Schneider,4 Suresh S. Ramalingam,5 Taofeek K. Owonikoko,5 H. Shelton Earp,6 Deborah DeRyckere,1 and Douglas K. Graham1

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Yan, D. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Huelse, J. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Kireev, D. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Tan, Z. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Chen, L. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Goyal, S. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Wang, X. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Frye, S. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Schneider, F. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Ramalingam, S. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by DeRyckere, D. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, United States of America

2Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America

4Department of Pathology, Emory University School of Medicine, Atlanta, United States of America

5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America

6Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Graham, D. in: JCI | PubMed | Google Scholar

Published June 16, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI150517.
Copyright © 2022, Yan 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 June 16, 2022 - Version history
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Abstract

Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, re-sensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K-AKT and MAPK-ERK signaling in parental cells, but only GAS6 activated these pathways in OSI resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naïve and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.

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