AXL,a member of the TAM receptor family,has emerged as a potential target for advanced-stage human malignancies.It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoti...AXL,a member of the TAM receptor family,has emerged as a potential target for advanced-stage human malignancies.It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoting pathways,including cancer cell proliferation,invasion,metastasis,epithelial-mesenchymal transition(EMT),angiogenesis,stemness,DNA damage response,acquired therapeutic resistance,immunosuppression,and inflammatory responses.Beyond oncology,AXL also facilitates viral infections,including SARS-CoV-2 and Zika highlighting its importance in both cancer and virology.In preclinical models,small-molecule kinase inhibitors targeting AXL have shown promising anti-tumorigenic potential.This review primarily focuses on the induction,regulation and biological functions of AXL in mediating these tumor-promoting pathways.We discuss a range of therapeutic strategies,including recently developed small-molecule tyrosine kinase inhibitors(TKIs),monoclonal antibodies,and antibody-drug conjugates(ADCs),anti-AXL-CAR,and combination therapies.These interventions are being examined in both preclinical and clinical studies,offering the potential for improved drug sensitivity and therapeutic efficacy.We further discuss the mechanisms of acquired therapeutic resistance,particularly the crosstalk between AXL and other critical receptor tyrosine kinases(RTKs)such as c-MET,EGFR,HER2/HER3,VEGFR,PDGFR,and FLT3.Finally,we highlight key research areas that require further exploration to enhance AXL-mediated therapeutic approaches for improved clinical outcomes.展开更多
基金supported by MK Bhan-Young Researcher Fellowship Programme(YRFP),Department of Biotechnology(DBT),Ministry of Science&Technology,Government of Indiasupported by MacNaught Fellowship at DFCI.T.K.Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE(2P50CA101942-16)and Program 5P30CA006516-56+2 种基金the Kohlberg Chair at Harvard Medical School and the Trust Family,Michael Brigham,Pan Mass Challenge,Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCINational Institutes of Health Grants(RO1 CA193675 and RO1 CA222355)the Dana-Farber/Harvard Cancer Centre(DF/HCC),Kidney Cancer SPORE,Career Enhancement Award(CEP)5P50CA101942-18 subaward.
文摘AXL,a member of the TAM receptor family,has emerged as a potential target for advanced-stage human malignancies.It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoting pathways,including cancer cell proliferation,invasion,metastasis,epithelial-mesenchymal transition(EMT),angiogenesis,stemness,DNA damage response,acquired therapeutic resistance,immunosuppression,and inflammatory responses.Beyond oncology,AXL also facilitates viral infections,including SARS-CoV-2 and Zika highlighting its importance in both cancer and virology.In preclinical models,small-molecule kinase inhibitors targeting AXL have shown promising anti-tumorigenic potential.This review primarily focuses on the induction,regulation and biological functions of AXL in mediating these tumor-promoting pathways.We discuss a range of therapeutic strategies,including recently developed small-molecule tyrosine kinase inhibitors(TKIs),monoclonal antibodies,and antibody-drug conjugates(ADCs),anti-AXL-CAR,and combination therapies.These interventions are being examined in both preclinical and clinical studies,offering the potential for improved drug sensitivity and therapeutic efficacy.We further discuss the mechanisms of acquired therapeutic resistance,particularly the crosstalk between AXL and other critical receptor tyrosine kinases(RTKs)such as c-MET,EGFR,HER2/HER3,VEGFR,PDGFR,and FLT3.Finally,we highlight key research areas that require further exploration to enhance AXL-mediated therapeutic approaches for improved clinical outcomes.
