Stanniocalcin 2-Induced Autophagy Confers Resistance of Lung Cancer Cells to EGFR Inhibition via the ERK/Beclin 1 Signaling.
Journal
Cancer medicine
Journal Volume
15
Journal Issue
5
Start Page
Article number e71874
ISSN
2045-7634
Date Issued
2026-05
Author(s)
Abstract
Background: Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are effective in treating NSCLC with EGFR mutations, the development of resistance limits their long-term efficacy. Autophagy has been implicated as a potential mechanism behind this acquired resistance. This study aims to investigate the role of Stanniocalcin 2 (STC2) in mediating autophagy and its contribution to EGFR TKI resistance. Methods: STC2 expression was manipulated to examine its effects on autophagy and EGFR TKI resistance both in vitro and in vivo. Autophagic activity was assessed by measuring LC3B-II expression levels, the number of LC3 puncta, and the accumulation of autophagic vacuoles. Pharmacological inhibitors and small interfering RNA (siRNA) were used to assess whether the regulatory relationship between STC2 and Beclin 1 was involved in STC2-mediated autophagy and EGFR TKI resistance. Results: Here, we found that STC2 was associated with increased autophagic activity, as evidenced by elevated LC3B-II levels, enhanced LC3 puncta formation, and increased accumulation of autophagic vacuoles. Conversely, STC2 knockdown resulted in reduced autophagic activity. We identified that STC2 is associated with ERK1/2 activation and Beclin 1–related autophagic activity. Importantly, inhibiting autophagy reversed the resistance to EGFR TKIs induced by STC2, as demonstrated in vitro and in vivo xenograft mouse models. Conclusion: These findings suggest that STC2 appears to promote cytoprotective autophagy, and targeting the STC2-associated ERK/Beclin 1 signaling axis may offer a promising strategy to overcome resistance to EGFR TKIs.
Subjects
AXL
EGFR TKI
autophagy
lung cancer
stanniocalcin 2
Type
journal article