Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer

Cisplatin-based chemotherapy remains a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC); however, the emergence of chemoresistance severely limits its clinical efficacy. Endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR) have been implicated in cancer cell survival and therapy resistance, highlighting modulation of this signalling as a potential therapeutic strategy. In this study, we investigated whether pharmacological induction of endoplasmic reticulum stress via sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition could attenuate cisplatin resistance in NSCLC. Using parental and cisplatin-resistant cell lines, we demonstrate that thapsigargin induces transcriptional responses consistent with endoplasmic reticulum stress, characterised by dynamic regulation of GRP78, PERK, XBP1, and ATF4 mRNA expression. Notably, thapsigargin pre-treatment significantly reduced cisplatin IC₅₀ values and decreased resistance indices in resistant cells, indicating attenuation of the resistant phenotype. In addition, SERCA inhibition enhanced apoptotic cell death in selected models and markedly suppressed clonogenic survival and migratory capacity across all cell lines examined. Distinct UPR-related transcriptional patterns were observed between parental and resistant cells, suggesting adaptive remodelling of ER stress signalling during acquisition of cisplatin resistance. Collectively, these findings identify ER calcium homeostasis as a modifiable determinant of platinum responsiveness and support targeting ER stress pathways as a potential adjunct strategy to improve therapeutic efficacy in chemoresistant NSCLC.