文章：

CCDC34通过β-连环蛋白介导的自噬维持干性表型，并促进肺腺癌对EGFR-TKI的耐药性

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

原文发布日期：2024-11-25 

英文摘要：

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.

摘要翻译：

尽管治疗策略近期取得进展，肺癌仍是全球癌症相关死亡的主要原因，严重威胁人类健康。肺腺癌（LUAD）作为肺癌最常见的组织学类型，在亚洲人群中有约40-50%的患者存在表皮生长因子受体（EGFR）突变。EGFR酪氨酸激酶抑制剂（EGFR-TKIs）的应用革命性地改善了EGFR突变型LUAD患者的预后，但获得性耐药仍是治疗失败的主要原因。因此，亟需新的治疗策略以解决LUAD患者对EGFR-TKIs的耐药问题。癌症干细胞相关因子会导致癌症治疗中的多重耐药（包括EGFR-TKI耐药）。卷曲螺旋结构域蛋白34（CCDC34）在多种癌症中充当致癌基因，但其在LUAD恶性进展中的作用及分子机制尚未见报道。本研究通过加权基因共表达网络分析（WGCNA）发现CCDC34可能与LUAD干细胞特性相关。进一步实验证明，CCDC34通过β-连环蛋白介导的ATG5诱导自噬调控机制促进LUAD干细胞特性，该机制在体外和体内实验中均有助于LUAD获得EGFR-TKI耐药性。敲低CCDC34可与EGFR-TKIs协同抑制肿瘤生长。本研究揭示了CCDC34与LUAD干细胞表型间的正相关性，为通过抑制CCDC34表达克服EGFR-TKI耐药提供了新见解。

原文链接：

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