Modes of resistance to anti-angiogenic therapy

Abstract

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF)-mediated pro-angiogenic signalling pathways are producing demonstrable clinical benefit for an increasing number of cancer types. However, in some cases (both in humans and in mouse models of cancer) anti-angiogenic therapies produce initial responses followed almost inevitably by progression, thereby affording appreciable but limited survival advantage. In other cases there is no objective benefit. Increasing evidence supports the proposition that progression and mortality following a period of benefit reflects an adaptive response by tumours, manifesting 'evasive resistance' to angiogenesis inhibitors. By contrast, patients for whom there is no tangible benefit indicate that an intrinsic resistance to angiogenesis inhibitors exists. Evasive resistance to VEGF pathway inhibitors (and arguably other angiogenesis inhibitors) involves a number of distinct and interrelated mechanisms that may be variably important. The emergent mechanisms of evasive resistance include revascularization consequent to upregulation of alternative pro-angiogenic signals; protection of the tumour vasculature either by recruiting pro-angiogenic inflammatory cells or by increasing protective pericyte coverage; accentuated invasiveness of tumour cells into local tissue to co-opt normal vasculature; and increased metastatic seeding and tumour cell growth in lymph nodes and distant organs. Intrinsic resistance is likely to involve similar molecular and cellular mechanisms to those that mediate evasive resistance. Whereas rapid adaptive responses (fast evasion) may underlie some cases of apparent intrinsic resistance, there is evidence to suggest that certain tumours, owing to their stage of progression, treatment history, genomic constitution and/or host genotype, may have a pre-existing tumour microenvironment that conveys such indifference. If the postulate of evasive and intrinsic resistance to angiogenesis inhibitors is further validated in preclinical and clinical investigations, we foresee a future of cancer therapeutics in which combinatorial strategies involving angiogenesis inhibition are integrated with drugs targeting resistance mechanisms to afford enduring efficacy.