CCDC34 maintains stemness phenotype through β-catenin-mediated autophagy and promotes EGFR-TKI resistance in lung adenocarcinoma.

Abstract

Despite recent advances in treatment strategy, lung cancer remains the leading cause of cancer-related mortality worldwide, and it is a serious threat to human health. Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, and approximately 40-50% of patients with LUAD in Asian populations have epidermal growth factor receptor (EGFR) mutations. The use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has revolutionarily improved the prognosis of patients with EGFR-mutated LUAD. However, acquired drug resistance is the main cause of treatment failure. Therefore, new therapeutic strategies are necessary to address the resistance to EGFR-TKIs in patients with LUAD. Cancer stemness-related factors lead to multiple-drug resistance in cancer treatment, including EGFR-TKI resistance. Coiled-coil domain-containing 34 (CCDC34) serves as an oncogene in several types of cancer. However, the role and molecular mechanism of CCDC34 in the malignant progression of LUAD have not been reported to date. In the present study, we found that CCDC34 may be associated with LUAD stemness through weighted gene co-expression network analysis (WGCNA). Furthermore, we demonstrated that CCDC34 promoted LUAD stemness properties through β-catenin-mediated regulation of ATG5-induced autophagy, which was conducive to acquired EGFR-TKI resistance in LUAD in vitro and in vivo. Knockdown CCDC34 can synergistically inhibit tumor growth when combined with EGFR-TKIs. This study reveals a positive association between CCDC34 and the stemness phenotype of LUAD, providing new insights into overcoming EGFR-TKI resistance in LUAD by inhibiting CCDC34 expression.