Pan Qianrong, Yang Xiangyu, Chen Zhuowen, Deng Quidi, Liu Jieyao, Ke Yuanyu, Lin Fangqin, Huang Wei, Lin Zhongxiao, Yu Xiyong, Lei Xueping
The Fifth Affiliated Hospital, Guangdong Province & NMPA & State Key Laboratory, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China; Guangdong provincial hospital of integrated Chinese and western medicine, Foshan 528200, China.
The Fifth Affiliated Hospital, Guangdong Province & NMPA & State Key Laboratory, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China.
Biochem Pharmacol. 2025 Oct;240:117067. doi: 10.1016/j.bcp.2025.117067. Epub 2025 Jun 23.
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors characterized with high incidence and mortality rate. Although many therapeutic agents have been applied for NSCLC therapy. However, majority patients inevitably suffer from chemoresistance after a period of therapy. Cancer stem-like cells (CSCs) are a critical factor for the chemoresistance in NSCLC. AXL is a member of the TAM family and its abnormal expression has been observed in NSCLC. Whereas, its role in the self-renewal of CSCs and Osimertinib resistance is still largely unknown. In this study, we showed that AXL was critical for the self-renewal ability of CSCs. AXL overexpression obviously promoted the self-renewal ability of CSCs and attenuated NSCLC cells sensitivity to Osimertinib. Whereas, AXL knockdown showed opposite effect. We also showed that AXL promoted CSCs properties partly dependent on stearoyl-CoA desaturase 1 (SCD1). SCD1 silence suppressed the CSCs properties of PC9 and NCI-H292 cells and increased their sensitivity to Osimertinib. SCD1 overexpression showed opposite effect on NCI-H460 and NCI-H1299 cells. Further research revealed that AXL might promoted SCD1 expression by up-regulating SREBP1, a critical transcription factor of SCD1. Moreover, targeting AXL with R428 significantly suppressed the self-renewal ability of CSCs and increased their sensitivity to Osimertinib. Taken these together, our study provides new insight into the role and mechanism of AXL in regulating NSCLC CSCs stemness. Our study also gives a new hint for the relationship between AXL and SCD1.
非小细胞肺癌（NSCLC）是最常见的恶性肿瘤之一，具有高发病率和死亡率的特点。尽管许多治疗药物已应用于NSCLC治疗。然而，大多数患者在一段时间的治疗后不可避免地会出现化疗耐药。癌症干细胞样细胞（CSCs）是NSCLC化疗耐药的关键因素。AXL是TAM家族的成员，其在NSCLC中存在异常表达。然而，其在CSCs自我更新和奥希替尼耐药中的作用仍 largely未知。在本研究中，我们表明AXL对CSCs的自我更新能力至关重要。AXL过表达明显促进了CSCs的自我更新能力，并减弱了NSCLC细胞对奥希替尼的敏感性。而AXL敲低则显示出相反的效果。我们还表明，AXL促进CSCs特性部分依赖于硬脂酰辅酶A去饱和酶1（SCD1）。SCD1沉默抑制了PC9和NCI-H292细胞的CSCs特性，并增加了它们对奥希替尼的敏感性。SCD1过表达对NCI-H460和NCI-H1299细胞显示出相反的效果。进一步的研究表明，AXL可能通过上调SCD1的关键转录因子SREBP1来促进SCD1的表达。此外，用R428靶向AXL显著抑制了CSCs的自我更新能力，并增加了它们对奥希替尼的敏感性。综上所述，我们的研究为AXL在调节NSCLC CSCs干性中的作用和机制提供了新的见解。我们的研究也为AXL与SCD1之间的关系提供了新的线索。
