RESTRICTING EXTRACELLULAR CA2+ ON GEFITINIB RESISTANT NON-SMALL CELL LUNG CANCER CELLS REVERSES ALTERED EPIDERMAL GROWTH FACTOR MEDIATED CA2+ RESPONSE, WHICH CONSEQUENTLY ENHANCES GEFITINIB SENSITIVITY

TOPIC: Lung Cancer TYPE: Original Investigations PURPOSE: Non-small cell lung cancer (NSCLC), one of the leading causes cancer-related death, has a low 5-year survival rate owing to inevitable acquired resistance toward antitumor drugs, platinum-based chemotherapy, and targeted therapy. Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling activates downstream events phospholipase C/inositol trisphosphate (IP3)/Ca2+ release from IP3-sensitive Ca2+ stores modulate proliferation, motility, invasion. However, role EGFR-mediated in drug is not fully understood. METHODS: We analyzed intracellular calcium ([Ca2+]i) signals PC-9 cells PC-9/GR (Gefitinib Resistant) under following conditions. observed hEGF (200ng/ml)-mediated [Ca2+]i oscillations response. Calcium influx, endoplasmic reticulum (ER) contents, (200 ng/ml)-mediated oscillations, effects inhibitors were studied absence extracellular ([Ca2+]e). compared gefitinib-induced cytotoxicity viability according presence or [Ca2+]e. RESULTS: NSCLC gefitinib resistant cells, we found that acute EGF treatment elicited but cells. presented more sustained basal level, lower higher spontaneous ([Ca2+]e) influx than Notably, restricting [Ca2+]e both types induced identical dependent on C EGFR activation. Consequently, upregulated gefitinib-mediated poly (ADP-ribose) polymerase cleavage, an increase Bax/Bcl-2 ratio, cytotoxicity, apoptosis. In addition, nuclear activated T (NFAT1) induction response was inhibited by whereas EGF-mediated NFAT1 regardless treatment. Restricting significantly reduced induction. CONCLUSIONS: These findings indicate plays pivotal developing suggest may be potential strategy for modulating drug-sensitivity. CLINICAL IMPLICATIONS: mechanism TKI DISCLOSURES: no disclosure file Misung Kim; Sohui Minsuk No relevant relationships Seihoon Yang, source=Web Response