Mechanisms of Acquired Resistance to Anti-VEGF Therapy for Neovascular Eye Diseases

Abstract

Purpose: The purpose of this study was to evaluate clinical reports of response-loss in patients with neovascular eye diseases, such as neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME), after repeated anti-vascular endothelial growth factor (VEGF) therapy. To assess experimental evidence of associations of other angiogenic growth factors and endothelial glycolytic pathways with the diseases and to propose the underlying mechanisms.

Methods: Review of published clinical studies and experimental investigations.

Results: Intravitreal injection of anti-VEGF biologic drugs (e.g. bevacizumab, ranibizumab, and aflibercept) is the front-line treatment for neovascular AMD and DME, and acts by halting the progression of excess blood vessel growth and leakage. Despite favorable clinical results, exudation returns in a number of patients after repeated administrations over time. Patients suffering from disease recurrence may have developed an acquired resistance to anti-VEGF therapy. We have analyzed clinical and preclinical findings on changes to angiogenic signaling pathways following VEGF-targeted treatment and hypothesize that switching to alternative pathways could potentially bypass VEGF blockade, accounting for development of resistance to anti-VEGF therapy. We have also discussed potential reprogramming of ocular endothelial glycolysis in response to VEGF antagonism and proposed that metabolic adaptations could impair blood-retinal barrier function, counteracting the clinical efficacy of VEGF-targeted therapies and contributing to a decline of response to them.

Conclusions: Future studies of the mechanisms proposed in this review may shed some light on how these adaptations result in the development of acquired resistance to anti-VEGF therapy, which should help discover new therapeutic strategies for overcoming anti-VEGF resistance and improving clinical efficacy.

Figure 1.

Neuropilin-1 (NRP-1) binding to multiple ligands and their potential involvement in anti-VEGF resistance. NRP-1 can function as a receptor for semaphorin 3A (SEMA3A) and a co-receptor for a variety of ligands, including vascular endothelial growth factor A (VEGF-A) through vascular endothelial growth factor receptor 2 (VEGFR2); transforming growth factor-βs (TGF-βs) through transforming growth factor-β receptors (TGF-βR); and platelet-derived growth factor (PDGF) through the platelet-derived growth factor receptor a (PDGFRα). Following anti-VEGF therapy, NRP-1-mediated VEGF-independent pathways may be switched on to bypass VEGF blockade for pathological angiogenesis and vascular permeability, accounting for disease recurrence due to the development of acquired resistance.

Figure 2.

Endothelial cell glycolysis and three glycolytic side pathways potentially influenced by anti-VEGF therapy. The glycolytic main pathway along with the pentose phosphate side pathway physiologically exist in ECs to allow energy production, biomass synthesis and redox homeostasis. The polyol side pathway and the methylglyoxal side pathway become pathologically significant during hyperglycemia. VEGF antagonism may cause EC oxidative stress and cellular damage through abolishment of VEGF-stimulated activity of glucose-6-phosphate dehydrogenase (G6PD) and depletion of reduced nicotinamide adenine dinucleotide phosphate (NADPH) in the pentose phosphate pathway, resulting in decreased reduced glutathione (GSH) and accumulated reactive oxygen species (ROS). Please note for simplicity, not all enzymes, metabolites and glycolysis side pathways are illustrated in this diagram. Abbreviations: 3DG, 3-deoxyglucosone; 3PG, 3-phosphoglycerate; ADP, adenosine diphosphate; AGE, advanced glycation end product; AR, aldose reductase; ATP, adenosine triphosphate; DHAP, dihydroxyacetone phosphate; F1,6P2, fructose 1,6-bisphosphate; F2,6P2, fructose-2,6-bisphosphate; F6P, fructose 6-phosphate; G3P, glyceraldehyde 3-phosphate; G6P, glucose 6-phosphate; GLUT1, glucose transporter 1; GSSG, oxidized glutathione; HK, hexokinase glucokinase; LDH, lactate dehydrogenase; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; PFK-1, 6-phosphofructo-1-kinase; PFKFB3, phosphofructokinase-2/fructose-2,6-bisphosphatase 3; PGK, phosphoglycerate kinase; R5P, ribose 5-phosphate; Ru5P, ribulose 5-phosphate; TK, transketolase.