AccScience Publishing / TD / Online First / DOI: 10.36922/TD025110019
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SHORT COMMUNICATION

Sorafenib generates microvesicle particles in non-small cell lung cancer

Yevgeniy Gladkiy1 ,  Anita Thyagarajan2* ,  Morgann Hendrixson1 ,  Ravi P. Sahu1*
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1 Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America
2 Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America
Tumor Discovery, 025110019 https://doi.org/10.36922/TD025110019
Received: 11 March 2025 | Revised: 30 April 2025 | Accepted: 7 May 2025 | Published online: 19 June 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Despite the improved clinical outcomes resulting from the use of sorafenib, the development of resistance mechanisms continues to undermine its treatment efficacy. Recent studies have implicated the role of a phospholipid mediator, platelet-activating factor receptor (PAFR) pathway, and extracellular vesicles known as microvesicle particles (MVP) in influencing cellular behavior and the efficacy of therapeutic agents. In this study, we determined the impact of the PAFR pathway and the acid sphingomyelinase (aSMase), which is required for the biogenesis of MVP, on sorafenib-induced effects on lung cancer growth and MVP release. Using A549 and H1299 non-small cell lung cancer (NSCLC) cell lines, we showed that sorafenib treatment reduced cell viability in a dose and time-dependent manner. Notably, sorafenib also enhanced MVP formation in both NSCLC cell lines. This MVP release was significantly attenuated by pharmacologic inhibition of the PAFR pathway through the WEB2086 compound and the aSMase inhibitor, imipramine, indicating the involvement of the PAFR and aSMase in sorafenib-induced MVP biogenesis. Moreover, co-treatment with imipramine enhanced the cytotoxic effects of sorafenib, suggesting that targeting MVP-associated pathways may improve sorafenib response. Collectively, these findings offer mechanistic insight into how sorafenib modulates MVP release and supports the therapeutic potential of combining tyrosine kinase inhibitors with agents that disrupt MVP biogenesis in NSCLC.

Keywords
Non-small cell lung cancer
Tyrosine kinase inhibitors
Sorafenib
Platelet-activating factor-receptor
Acid sphingomyelinase
Microvesicle particles
Funding
The financial support from the BSOM Medical Student Research Grant (Y.G. and M.H. with A.T. and R.P.S. as mentors) and the NIH R21 grant ES033806 (R.P.S.) are greatly appreciated.
Conflict of interest
Ravi P. Sahu is an Editorial Board Member of this journal, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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