development of quinazoline-tetrahydrofuranyl-pyridinyl hybrids as dual egfr and her2 inhibitors to combat lapatinib resistance in breast cancer

Lapatinib resistance in her2-positive breast cancer poses a major therapeutic challenge. in this study, we developed novel quinazoline-tetrahydrofuranyl-pyridinyl hybrids as dual egfr and her2 inhibitors to address this resistance. among the synthesized compounds, compounds 13e, 13i, and 13j were selected for detailed in vitro evaluation. 13i exhibited superior dual inhibitory activity, with ic50 values of 27.4 ± 1.8 nm for egfr and 18.2 ± 1.9 nm for her2, outperforming lapatinib (ic50:29.7 ± 1.3 nm for egfr, 19.3 ± 1.5 nm for her2). in cytotoxicity assays, 13i demonstrated potent antiproliferative effects, with ic50 values of 1.95 ± 0.17 µm in bt-474, 2.55 ± 0.23 µm in skbr3, and 5.92 ± 0.26 µm in lapatinib-resistant lap-skbr3 cells, compared to lapatinib’s 21.6 ± 1.54 µm in lap-skbr3. apoptosis assays revealed that 13i induced late apoptosis in 51.3 ± 4.4% of lap-skbr3 cells, which was significantly higher than lapatinib’s 15.2 ± 1.4%. dna fragmentation assays confirmed extensive genomic cleavage in resistant cells treated with 13i, in contrast to the marginal effects of lapatinib. additionally, 13i at 2xic₅₀ reduced migration and invasion in lap-skbr3 cells to levels significantly lower than lapatinib at ic50, with a dose-dependent decrease in migrated and invaded cells. western blot analysis showed that 13i markedly reduced p-egfr, p-her2, and p-erk1/2 levels in lap-skbr3 cells compared with lapatinib, confirming robust pathway inhibition. these findings highlight 13i’s potent anti-tumor activity via dual kinase inhibition, apoptosis induction, and metastasis suppression, making it a promising candidate for further preclinical studies on lapatinib-resistant her2-positive breast cancer.