A fibroblast activation protein degrader enhances cisplatin sensitivity in non‑small cell lung cancer

The therapeutic effect of cisplatin against non‑small cell lung cancer (NSCLC), the most common lung cancer, is limited by resistance. In the present study, a fibroblast activation protein (FAP) degrader (Pomalidomide‑PEG2‑FAP2286: FAP‑D) was utilized to enhance cisplatin sensitivity in NSCLC. The study specifically assessed the viabilities of NCI‑H1299 and NCI‑H460 cells (human NSCLC cell lines) and the growth of heterogeneous tumors in mice. The binding between FAP‑D and FAP was studied by molecular docking. The ability of FAP‑D to induce FAP and CD26 degradation was examined by western blotting, as was caspase‑3 and cleaved caspase‑3 expression. The viabilities of H1299 and H460 cells were analyzed using a Cell Counting Kit‑8 assay (CCK‑8). Cell migration rates were studied via wound‑healing assays. Apoptotic features were confirmed in tumors by hematoxylin‑eosin staining assay. FAP was degraded by FAP‑D in a time‑ and concentration‑dependent manner, whereas CD26 protein expression was not altered by FAP‑D. FAP‑D exhibited favorable biocompatibility. The half‑maximal inhibitory concentration (IC₅₀) of cisplatin was reduced by co‑treatment with FAP‑D, which could be attributable to the inhibition of cell migration by FAP‑D. Heterogeneous tumor growth was also strongly suppressed by cisplatin + FAP‑D. The apoptotic features of H1299/H460 cells and tumors were enhanced by cisplatin + FAP‑D treatment. In conclusion, the study demonstrated that FAP‑D can enhance the cisplatin sensitivity of H1299 cells and NSCLC tumors. The present findings shed new light into promising treatment strategies and demonstrated the potential clinical utility of cisplatin + FAP‑D for NSCLC treatment.