Sun Xia, Jia Lizhou, Wang Tengqi, Zhang Yulian, Zhao Wei, Wang Xiangcheng, Chen Hao
Emergency Center, Bayannur Hospital, Bayannur, Inner Mongolia, 015000, China.
Department of Pathology, Wannan Medical College, Wuhu, Anhui, 241002, China.
J Cancer. 2021 Jul 3;12(17):5310-5319. doi: 10.7150/jca.57711. eCollection 2021.
Gefitinib has shown good efficacy in treating recurrent or advanced non-small cell lung cancer (NSCLC), but the drug resistance remains a clinical challenge in medical oncology. In addition, the complex interaction between tumor cells and heterogeneous stromal cells in the adjacent tumor microenvironment (TME) is also an important contributor to drug resistance. So, it is very necessary to detect the related target genes before and after gefitinib treatment dynamically. In this study, the relationship between Trop2 and gefitinib resistance in NSCLC was investigated, and the underlying mechanism was explored. Results showed that Trop2 was associated with EGFR gene mutation and drug resistance in clinical tissues. Trop2 was confirmed to induce gefitinib resistance in NSCLC, and Trop2 binding IGF2R promoted the IGF2-IGF1R-Akt axis to enhance gefitinib resistance and remodeling the TME in NSCLC. Notably, silencing of Trop2 in cancer cells combined with IGF1R inhibitor significantly decreased the proliferation of tumor cells and reshaped the NSCLC TME and , including the recruitment of macrophages. These findings deepened the understanding of the function of Trop2 and the involved mechanisms of gefitinib resistance, and may provide new molecular targets for NSCLC with gefitinib resistance.
吉非替尼在治疗复发或晚期非小细胞肺癌（NSCLC）方面已显示出良好疗效，但耐药性仍是医学肿瘤学中的一项临床挑战。此外，肿瘤细胞与相邻肿瘤微环境（TME）中异质性基质细胞之间的复杂相互作用也是耐药性的一个重要因素。因此，动态检测吉非替尼治疗前后的相关靶基因非常必要。在本研究中，我们调查了Trop2与NSCLC中吉非替尼耐药性之间的关系，并探索了其潜在机制。结果显示，Trop2与临床组织中的EGFR基因突变及耐药性相关。已证实Trop2可诱导NSCLC中的吉非替尼耐药，且Trop2结合IGF2R可促进IGF2-IGF1R-Akt轴，增强NSCLC中的吉非替尼耐药性并重塑TME。值得注意的是，癌细胞中Trop2的沉默与IGF1R抑制剂联合使用可显著降低肿瘤细胞的增殖，并重塑NSCLC TME，包括巨噬细胞的募集。这些发现加深了对Trop2功能及吉非替尼耐药相关机制的理解，并可能为具有吉非替尼耐药性的NSCLC提供新的分子靶点。
