Harnessing cell-surface CD26 proteolysis-targeting chimeras for molecular targeted therapy against non-small cell lung cancer

Molecular targeted therapy (MTT) for non-small cell lung cancer (NSCLC) has been a central issue for a long time. However, drug resistance and extra toxicity have limited its further clinical applications. Herein, taking advantages of the proteolysis-targeting chimeras (PROTACs), a series of PROTAC degraders ( P4-1 to 4 ) targeting cell-surface CD26 (a potential target for NSCLC) have been developed for MTT of NSCLC. To achieve the efficient degradation of cell surface proteins, which is a huge challenge, the molecular structures of degraders were rational designed and optimized. Remarkably, CD26 can be degraded by P4-3 evidently at low dose (~ 500 nM) without degrading CD26 isoenzymes, which was independent of autophagy pathway. Surprisingly, the proliferation of representative NSCLC cells (NCl-H460 and NCl-H1299 cells) and tumors were significantly inhibited by P4-3 , and no toxicity of P4-3 for BEAS-2B cells (human lung normal epithelial cells) were obtained. More interestingly, the powerful proliferation inhibition capabilities of P4-3 for organoids were observed. Moreover, a mechanism of P4-3 for treatment of NSCLC was proposed, which is the degradation of CD26 that induce the mitochondria-mediated apoptosis of NSCLC cells, tumors and organoids. Our exciting findings put forward instructive thoughts for the development of promising treatment strategies for NSCLC.