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Tumor Discovery

SHORT COMMUNICATION
Sorafenib generates microvesicle particles in

non-small cell lung cancer

2
Yevgeniy Gladkiy 1 , Anita Thyagarajan * , Morgann Hendrixson 1 , and
Ravi P. Sahu *
1
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
(This article belongs to the Special Issue: New Developments in Lung Cancer Research, Diagnosis,
Treatment, and Prognosis)

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
*Corresponding authors: MVP, on sorafenib-induced effects on lung cancer growth and MVP release. Using
Anita Thyagarajan A549 and H1299 non-small cell lung cancer (NSCLC) cell lines, we showed that
(anita.thyagarajan@wright.edu) sorafenib treatment reduced cell viability in a dose and time-dependent manner.
Ravi P. Sahu
(ravi.sahu@wright.edu) Notably, sorafenib also enhanced MVP formation in both NSCLC cell lines. This
MVP release was significantly attenuated by pharmacologic inhibition of the PAFR
Citation: Gladkiy Y, Thyagarajan A, pathway through the WEB2086 compound and the aSMase inhibitor, imipramine,
Hendrixson M, Sahu RP. Sorafenib
generates microvesicle particles in indicating the involvement of the PAFR and aSMase in sorafenib-induced MVP
non-small cell lung cancer. Tumor biogenesis. Moreover, co-treatment with imipramine enhanced the cytotoxic
Discov. 2025;4(3):81-91. effects of sorafenib, suggesting that targeting MVP-associated pathways may
doi: 10.36922/TD025110019
improve sorafenib response. Collectively, these findings offer mechanistic insight
Received: March 11, 2025 into how sorafenib modulates MVP release and supports the therapeutic potential
Revised: April 30, 2025 of combining tyrosine kinase inhibitors with agents that disrupt MVP biogenesis in
NSCLC.
Accepted: May 7, 2025
Published online: June 19, 2025
Keywords: Non-small cell lung cancer; Tyrosine kinase inhibitors; Sorafenib; Platelet-
Copyright: © 2025 Author(s).
This is an Open-Access article activating factor-receptor; Acid sphingomyelinase; Microvesicle particles
distributed under the terms of the
Creative Commons Attribution
License, permitting distribution,
and reproduction in any medium, 1. Introduction
provided the original work is
properly cited. Lung cancer is the leading cause of cancer-related mortality in the United States and
1
Publisher’s Note: AccScience worldwide. It is estimated that 234,580 new cases and 125,070 deaths (~20% of all
Publishing remains neutral with cancer-related deaths) are attributed to lung cancer. Of the two subtypes, non-small
2
regard to jurisdictional claims in 2
published maps and institutional cell lung cancer (NSCLC) accounts for about 80 – 85% of all lung cancer cases. The
affiliations. management of NSCLC includes chemotherapy, immunotherapy, and targeted treatments

Volume 4 Issue 3 (2025) 81 doi: 10.36922/TD025110019