Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, 322000, China.
School of Medicine, Zhejiang University, Hangzhou, 323000, China.
Cancer Lett. 2022 Apr 28;532:215583. doi: 10.1016/j.canlet.2022.215583. Epub 2022 Feb 9.
Drug resistance reflects the evolution of tumors, which is the main cause of recurrence and death. Currently, EGFR-TKI treatment is the first-line therapy for lung adenocarcinoma (LUAD) patients. Although EGFR-TKI achieved good effects at the beginning, most of the LUAD patients eventually acquired resistance. Therefore, it's urgently need to develop a strong criterion for identifying these patients who may benefit from additional therapy. In this study, we established a three TKI resistant-related gene signature (DDIT4, OAS3, FSCN1), and determined that's an accuracy, independent and specific prognostic model for LUAD patients. Patients categorized as high-risk by this signature showed more sensitive to chemotherapy, and exhibited higher expression of common immune checkpoints such as PD-L1/B7H3/PD-L2/IDO1. Moreover, these patients were characterized by increased infiltration of M0 macrophage and activated memory CD4 T cells. The expression and prognostic values of DDIT4, FSCN1 and OAS3 were further confirmed in clinical data. In addition, experimental data showed that FSCN1 promoted LUAD development via PI3K/AKT signaling. In conclusion, this signature is highly predictive of prognostic in LUAD patients, and may serve as a powerful prediction tool for LUAD patients to further choose chemo- and immunotherapies.
耐药性反映了肿瘤的进化，是肿瘤复发和死亡的主要原因。目前，EGFR-TKI 治疗是肺腺癌（LUAD）患者的一线治疗方法。虽然 EGFR-TKI 最初效果良好，但大多数 LUAD 患者最终都产生了耐药性。因此，迫切需要制定一个强有力的标准来识别可能从额外治疗中获益的这些患者。在本研究中，我们建立了一个与三种 TKI 耐药相关的基因特征（DDIT4、OAS3、FSCN1），并确定这是一个对 LUAD 患者具有准确性、独立性和特异性的预后模型。通过该特征分类为高风险的患者对化疗更敏感，并且表现出更高表达常见免疫检查点，如 PD-L1/B7H3/PD-L2/IDO1。此外，这些患者的特征是 M0 巨噬细胞和激活的记忆 CD4 T 细胞浸润增加。在临床数据中进一步证实了 DDIT4、FSCN1 和 OAS3 的表达和预后价值。此外，实验数据表明 FSCN1 通过 PI3K/AKT 信号通路促进 LUAD 的发展。总之，该特征对 LUAD 患者的预后具有高度预测性，可能成为 LUAD 患者进一步选择化疗和免疫治疗的有力预测工具。
