Targeting vascular endothelial growth factor and its receptors in non-small cell lung cancer for improved treatment strategies

Non-small cell lung cancer (NSCLC) is responsible for about 85% of all lung cancers and is a major contributor to cancer deaths worldwide. Angiogenesis, mainly mediated by vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), is a key factor involved in the progression and metastasis of NSCLCs and the development of drug resistance. Anti-angiogenic therapy, for instance, with monoclonal antibodies like bevacizumab and ramucirumab, as well as multi-targeted tyrosine kinase inhibitors (TKIs) like nintedanib and anlotinib has been shown to improve the management of NSCLC. Despite the improvement in the management, patients develop resistance through mechanisms such as hypoxia signaling, alternative angiogenic factor activation, vascular structure remodeling, and a suppressive tumor microenvironment (TME). Recent studies have revealed the use of a combination of anti-angiogenic therapy and immune checkpoint blockade to normalize the tumor vasculature, thus enhancing treatment efficacy. Angiogenesis-associated biomarkers, despite extensive research, have not been seen to have a clinical impact in the management and treatment of NSCLC because of the heterogeneous characteristics and the dynamic regulation of the cascade. This review summarizes current VEGF/VEGFR-targeted therapies in NSCLC, mechanisms of resistance, and future directions toward biomarker-guided therapeutic optimization.