Cancer/testis antigen CAGE mediates Osimertinib Resistance in Non-small cell lung cancer cells and predicts poor Prognosis in Patients with Pulmonary adenocarcinoma

Abstract

Purpose CAGE, a cancer/testis antigen, was originally isolated from the sera of patients with gastric cancers. We have shown the role of CAGE in resistance to chemotherapy and target therapy. In this study, we wanted to investigate the possible role of CAGE in osimertinib, an inhibitor of EGFR tyrosine kinase. Methods The clinicopathological correlation with CAGE and autophagy flux in patients was examined using immunohistochemistry and in situ hybridization. The evaluation of autophagy in osimertinib resistance was analyzed using immune-blot, Immuno-cell chemistry and immuno-histochemistry in vitro and in vivo. Results Here, we found that IHC showed the expression of CAGE in more than 50% of patients with pulmonary adenocarcinomas (pADCs). The expression of CAGE was increased in pADCs after the acquisition of EGFR-TKIs resistance. High expression of CAGE was correlated with shorter overall survival (OS) and progression free survival (PFS) in patients with pADCs. Thus, CAGE mediates osimertinib resistance and predicts poor prognosis in patients with pADCs. Osimertinib-resistant non-small cell lung cancer cells (PC-9/OSI) were established. Mechanistic studies of CAGE-mediated osimertinib resistance were performed. PC-9/OSI cells showed increased autophagic flux and CAGE expression compared with parental sensitive PC-9 cells. PC-9/OSI cells showed higher tumorigenic, metastatic, and angiogenic potential compared with parental PC-9 cells. CAGE CRISPR-Cas9 cell lines showed decreased autophagic flux, invasion, migration potential, and tumorigenic potential compared with PC-9/OSI cells in vitro and in vivo. Conclusion Collectively, our data suggest that CAGE plays a crucial role in the progression of tumorigenesis and metastasis by modulating autophagy. Furthermore, our findings propose the inhibition of CAGE as a potential therapeutic strategy for osimertinib resistance.