MERTK activation drives osimertinib resistance in <i>EGFR</i>-mutant non-small cell lung cancer

Dan Yan; Justus M. Huelse; Dmitri Kireev; Zikang Tan; Luxiao Chen; Subir Goyal; Xiaodong Wang; Stephen V. Frye; Madhusmita Behera; Frank Schneider; Suresh S. Ramalingam; Taofeek K. Owonikoko; H. Shelton Earp; Deborah DeRyckere; Douglas K. Graham

doi:10.1172/JCI150517

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

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

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 (EGFR^MT) 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 EGFR^MT 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 EGFR^MT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFR^MT NSCLC.

Version 1 (June 16, 2022): In-Press Preview

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

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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

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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