Effects of Benzo[a]pyrene on Targeted Therapy Response and Platelet-Activating Factor-Receptor-Mediated Microvesicle Particle Release in Non-Small Cell Lung Cancer

Background/Objectives: Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, driven by invasive behavior and frequent resistance to systemic therapies. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) benefit patients with EGFR-mutant NSCLC, but their efficacy is often limited by tumor-intrinsic and environmental resistance mechanisms. Benzo[a]pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon from tobacco smoke, combustion, and dietary sources, is a known carcinogen; however, its role in modulating therapeutic responses is poorly understood. Studies, including ours, implicate the platelet-activating factor-receptor (PAFR) pathway in mediating environmental pollutant and therapy-induced effects on tumor growth and microvesicle particle (MVP) release. We hypothesized that PAFR activation mediates BaP-induced NSCLC progression and influences EGFR-TKI responses. Methods: We assessed the effects of BaP, PAFR agonist CPAF, EGFR-TKIs, and their combinations on cell viability, proliferation, migration, anchorage-independent growth, and MVP secretion. Results: BaP did not alter cell survival but significantly increased migration, growth, colony formation, and MVP release, similar to CPAF, and these effects were blocked by a PAFR antagonist or acid sphingomyelinase inhibitor. Notably, BaP did not significantly reduce EGFR-TKI efficacy at tested concentrations. Conclusions: These results show that environmental carcinogens modulate NSCLC behavior through PAFR signaling without compromising EGFR-TKI responsiveness, highlighting PAFR as a potential therapeutic target.