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ResearchIn-Press PreviewCell biologyClinical ResearchOncology Open Access | 10.1172/JCI198418

Osimertinib activates a TGFβ2-dependent secretory program that drives lung adenocarcinoma progression

Madhurima Ghosh,1 Chao Wu,1 Abhishek Kumar,1 Monique B. Nilsson,1 John V. Heymach,1 Weina Zhao,1 Jiang Yu,1 Xin Liu,1 Na Ding,1 Shike Wang,3 Guan-Yu Xiao,4 Angelo Chen,5 Kate V. Grimley,6 William K. Russell,7 Chad J. Creighton,8 Xiaochao Tan,3 and Jonathan M. Kurie1

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

Find articles by Wu, C. in: PubMed | Google Scholar

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

Find articles by Zhao, W. in: PubMed | Google Scholar

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

Find articles by Xiao, G. in: PubMed | Google Scholar |

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

Find articles by Russell, W. in: PubMed | Google Scholar |

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

Find articles by Creighton, C. in: PubMed | Google Scholar |

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Canada

3Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

4Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, United States of America

5Department of Biosciences, Rice University, Houston, United States of America

6Department of Chemistry, Texas A&M University, College Station, United States of America

7Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America

8Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States of America

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

Published December 9, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI198418.
Copyright © 2025, Ghosh 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 December 9, 2025 - Version history
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Abstract

EGFR-mutant lung adenocarcinomas (LUADs) that are vulnerable to the EGFR antagonist Osimertinib (Osi) eventually relapse owing in part to the emergence of drug tolerant persister (DTP) cells that arise through epigenetic mechanisms. Intra-tumoral DTP cells can herald a worse clinical outcome, but the way in which DTP cells influence LUAD progression remains unclear. Osi-resistant (OR) cells exhibit typical DTP cell features, including a propensity to undergo senescence and epithelial-to-mesenchymal transition (EMT), which can activate heightened secretory states. Therefore, we postulated that OR cells influence LUAD progression through paracrine mechanisms. To test this hypothesis, we utilized congenic pairs of EGFR-mutant LUAD cell lines in which drug naive (DN) cells were rendered OR by chronic exposure to escalating doses of Osi. Co-cultured in vitro or co-injected into mice, paracrine signals from OR cells enhanced the growth and metastatic properties of DN cells. EMT and senescence activated non-overlapping secretomes, and OR cells governed DN cells by undergoing EMT but not senescence. Mechanistically, Osi rapidly increased TGFβ2 levels to initiate EMT, which triggered a Golgi remodeling process that accelerated the biogenesis and anterograde trafficking of secretory vesicles. The pro-tumorigenic activity of OR cells was diminished by depletion of EMT-dependent secreted proteins or the EMT-activating transcription factor ZEB1. These findings identify paracrine mechanisms by which OR cells drive LUAD progression.

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