A new anilinoquinazoline derivative, F307 induces autophagy and differential apoptosis in wild-type and mutated-epidermal growth factor receptor non-small cell lung cancer cell lines

Non-small-cell lung cancer (NSCLC) often develops epidermal growth factor receptor (EGFR) mutations that respond poorly to chemotherapy with complicated resistance mechanisms, limiting the long-term treatment success. This study is to determine the functional impact and molecular mechanisms of the F307 compound in NSCLC cell lines harboring either wild-type or mutant EGFR. Cell proliferation in NSCLC cell lines was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays in a time- and dose-dependent manner. Apoptosis and cell cycle distribution were analyzed via flow cytometry, supported by caspase activity assays and morphological evaluations. Western blotting was used to quantify key proteins involved in cell cycle regulation, autophagy, apoptosis, and EGFR signaling. F307, a new anilinoquinazoline derivative, demonstrated potent antiproliferative effects in a time- and dose-dependent manner. It induced autophagic activity in both A549 and H1975 cells. In A549 cells, F307 promoted caspase-dependent apoptosis via the intrinsic mitochondrial pathway, whereas in H1975 cells via a caspase-independent mechanism, characterized by poly (ADP-ribose) polymerase cleavage. This is accompanied by increased p53 expression in A549 and decreased mutant p53 levels in H1975 cells. Cell cycle analysis revealed G2/M phase arrest in both cell lines, with increased p21 expression. F307 effectively inhibited EGFR phosphorylation and downstream phosphoinositide 3-kinase signaling, leading to reduced extracellular signal-regulated kinase and protein kinase B phosphorylation in A549 cells and elevated levels in H1975 cells. This study highlights EGFR as a key target in NSCLC and provides additional insights of F307's antitumor activity, but further improvement to the compound and biological studies are needed to uncover its potential for further therapeutic development.