Artesunate overcomes icotinib resistance in non-small cell lung cancer with <i>EGFR</i>-sensitive mutations

Abstract Objectives Due to increasing severity of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR -mutant non-small cell lung cancer (NSCLC) patients, this study investigated whether artesunate overcomes such resistance specifically to icotinib hydrochloride (icotinib) and explored its mechanisms. Methods We evaluated anti-tumor effects of artesunate in icotinib- and cross-resistant NSCLC models (NCI-H1975, PC-9/GR cells, and NCI-H1975 xenografts). Effects of GAB1 knockdown/overexpression and artesunate on EGFR–Gab1–SHP2–ERK and EGFR–PI3K pathways were analyzed. Clinical correlations between Gab1 and phosphorylated Gab1 (pGab1) expressions and outcomes were analyzed in specimens. Results Artesunate significantly inhibited proliferation and induced apoptosis in resistant EGFR -mutant/T790M+ models. Gab1 overexpression characterized icotinib-resistant cells. GAB1 knockdown suppressed SHP2/phosphorylated ERK (pERK) expression, reducing proliferation and promoting apoptosis. Rescue experiments confirmed that GAB1 overexpression promoted proliferation and suppressed apoptosis via ERK activation. Artesunate downregulated phosphorylated EGFR (pEGFR), pGab1, SHP2, pERK1/2, and total EGFR/Gab1. Downregulated pGab1 was correlated with improved efficacy of first-line EGFR-TKIs and patient prognosis. Patients with low pGab1 expression exhibited significantly prolonged median progression-free survival (PFS; 17.3 vs. 8.8 months, HR=0.345, p&lt;0.001) and a significantly elevated objective response rate (ORR; 83.9 % vs. 31.0 %, p&lt;0.001) compared to those with high pGab1 expression. Conclusions Artesunate overcomes icotinib resistance in NSCLC through suppression of proliferation and activation of apoptosis via the EGFR–Gab1–SHP2–ERK axis. Gab1 regulates resistance via SHP2–ERK, highlighting its therapeutic potential. These findings support artesunate as a clinically translatable agent for overcoming resistance of first-generation EGFR-TKIs.