Unlocking Spondin-1 and Spondin-2 as Ultrasound-Responsive Biomarkers in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: Diagnostic and Therapeutic Perspectives

The development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) remains a huge challenge in treating EGFR-mutant non-small-cell lung cancer (NSCLC). Recent improvements in ultrasound-based cancer biotherapies have necessitated the discovery of responsive molecular targets that can improve therapeutic accuracy. This study looks at the diagnostic usefulness and functional importance of spondin-1 (SPON1) and spondin-2 (SPON2) in EGFR-mutated NSCLC, with a focus on their possible response to ultrasound-enhanced therapies. Plasma levels of SPON1 and SPON2 were considerably higher in EGFR-mutant NSCLC patients than in healthy controls. Receiver operating characteristic curve analysis demonstrated that both proteins had good sensitivity and specificity. SPON1 and SPON2 expression were linked with aggressive clinical characteristics such as tumor size (≥5 cm), advanced TNM stage (III-IV), and lymph node involvement. Importantly, both markers were significantly elevated in gefitinib-resistant, EGFR-mutant NSCLC cells. Functional investigations revealed that suppressing SPON1 and SPON2 reversed resistance by inhibiting proliferation and invasion while increasing apoptosis. In contrast, overexpression conferred resistance to gefitinib in parental cells. Given their dual roles in diagnosis and resistance, SPON1 and SPON2 are intriguing ultrasound-responsive biomarkers in EGFR-mutant NSCLC. These findings provide the groundwork for future incorporation of ultrasound-mediated delivery methods or sonodynamic treatments targeting SPON1/SPON2, opening up new possibilities for overcoming EGFR-TKI resistance and improving therapeutic effectiveness in resistant NSCLC.