AXL enhances the self-renewal of cancer stem-like cells and Osimertinib chemoresistance by regulating SCD1 in non-small cell lung cancer.

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 PC9AXL vector and NCI-H292AXL vector cells and increased their sensitivity to Osimertinib. SCD1 overexpression showed opposite effect on NCI-H460shAXL and NCI-H1299shAXL 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.