Osimertinib activates a TGF-β2-dependent secretory program that drives lung adenocarcinoma progression

Authors

• Madhurima Ghosh, University of Texas MD Anderson Cancer Center
• Chao Wu, University of Texas MD Anderson Cancer Center
• Abhishek Kumar, University of Texas MD Anderson Cancer Center
• Monique Nilsson, University of Texas MD Anderson Cancer Center
• John V. Heymach, University of Texas MD Anderson Cancer Center
• Weina Zhao, University of Texas MD Anderson Cancer Center
• Jiang Yu, University of Texas MD Anderson Cancer Center
• Xin Liu, University of Texas MD Anderson Cancer Center
• Na Ding, University of Texas MD Anderson Cancer Center
• Shike Wang, Tulane University School of Medicine
• Guan Yu Xiao, University of KentuckyFollow
• Angelo Chen, Rice University
• Kate Grimley, Texas AandM University
• William K. Russell, University of Texas Medical Branch at Galveston
• Chad J. Creighton, Baylor College of Medicine
• Xiaochao Tan, Tulane University School of MedicineFollow
• Jonathan M. Kurie, University of Texas MD Anderson Cancer CenterFollow

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. Intratumoral 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-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. Cocultured in vitro or coinjected into mice, paracrine signals from OR cells enhanced the growth and metastatic properties of DN cells. EMT and senescence-activated nonoverlapping secretomes, and OR cells governed DN cells by undergoing EMT but not senescence. Mechanistically, Osi rapidly increased TGF-β2 levels to initiate EMT, which triggered a Golgi remodeling process that accelerated the biogenesis and anterograde trafficking of secretory vesicles. The protumorigenic 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.

Document Type

Article

Publication Date

2-2-2026

Digital Object Identifier (DOI)

10.1172/JCI198418

Archival?

Archival

Repository Citation

Ghosh, Madhurima; Wu, Chao; Kumar, Abhishek; Nilsson, Monique; Heymach, John V.; Zhao, Weina; Yu, Jiang; Liu, Xin; Ding, Na; Wang, Shike; Xiao, Guan Yu; Chen, Angelo; Grimley, Kate; Russell, William K.; Creighton, Chad J.; Tan, Xiaochao; and Kurie, Jonathan M., "Osimertinib activates a TGF-β2-dependent secretory program that drives lung adenocarcinoma progression" (2026). Markey Cancer Center Faculty Publications. 521.
https://uknowledge.uky.edu/markey_facpub/521