TY  - JOUR
T1  - Targeting Gefitinib-Resistant EGFR Mutants with Narciclasine in Non–Small Cell Lung Cancer
A1  - Yuki Haruto Tanaka
A1  - Kenta Naoki Sato
JF  - Journal of Medical Sciences and Interdisciplinary Research
JO  - J Med Sci Interdiscip Res
SN  - 3108-4826
Y1  - 2022
VL  - 2
IS  - 1
DO  - 10.51847/iOdIctHVaP
SP  - 99
EP  - 116
N2  - Non-small cell lung cancer (NSCLC) involves aberrant epidermal growth factor receptor (EGFR) activation resulting from overexpression or mutations. Although EGFR tyrosine kinase inhibitors (TKIs) like gefitinib are employed in NSCLC therapy, resistance frequently emerges through secondary EGFR mutations or bypass signaling pathways. Thus, new agents capable of bypassing EGFR-TKI resistance are essential for improved NSCLC management. Narciclasine (Ncs) is a cytotoxic alkaloid derived from Narcissus species that demonstrates antitumor and anti-inflammatory properties.Cell viability was determined via trypan blue staining and Live/Dead assay. The antiproliferative activity of Ncs was examined using the WST-1 assay and cell cycle profiling in several NSCLC lines, including A549 and H1299 (wild-type EGFR), gefitinib-resistant H1975 (L858R/T790M-EGFR), gefitinib-sensitive PC-9 (exon 19 deletion-EGFR), and the gefitinib-resistant PC-9 derivative, PC-9-GR. Molecular docking simulations explored Ncs interaction with wild-type and mutant EGFR forms. The impact of Ncs on EGFR kinase function was tested in vitro using wild-type EGFR and L858R/T790M-EGFR. In vivo antitumor activity of Ncs was evaluated in a C. elegans model expressing L858R/T790M-EGFR and in mouse xenografts of A549 and H1975 cells. Tumor tissues underwent histological examination for EGFR, phosphorylated EGFR, and phosphorylated STAT3 expression.Ncs displayed potent growth suppression across diverse NSCLC lines, encompassing gefitinib-sensitive A549, H1299, and PC-9 cells as well as gefitinib-resistant H1975 and PC-9-GR cells. Remarkably, Ncs achieved an IC50 of 22 nM in H1975 cells harboring the gefitinib-resistant EGFR mutant, substantially lower than in other lines. Ncs strongly provoked G2/M phase arrest in H1975 cells. Docking studies indicated Ncs binding to both wild-type and mutant EGFR, with preferential inhibition of L858R/T790M-EGFR kinase activity over wild-type EGFR. In the C. elegans model, Ncs attenuated the tumor-like multivulva phenotype. Ncs administration reduced tumor progression in mice bearing A549 or H1975 xenografts and decreased EGFR, p-EGFR, and p-STAT3 levels in tumor samples. These findings indicate that Ncs exerts anticancer effects through suppression of EGFR function and associated downstream pathways. This action is especially pronounced in EGFR mutants conferring TKI resistance, including to gefitinib, highlighting Ncs as a promising candidate for treating TKI-resistant NSCLC.
UR  - https://smerpub.com/article/targeting-gefitinib-resistant-egfr-mutants-with-narciclasine-in-nonsmall-cell-lung-cancer-bwbenuimklfhox4
ER  -