Tumor growth requires induction of an angiogenic program, and targeting of this program with antiangiogenic drugs shows an impact on tumor progression. However, although they are effective at reducing angiogenesis, these therapies have not produced widespread or enduring clinical benefi t, which openly exposes their limitations. Here, we describe the current limitations of these therapies, including the known mechanisms and current controversies. Further, we present some of the recent approaches to predict these limitations and strategies to overcome them. With the development of meaningful predictive biomarkers and effective treatments that impede these limitations, longer and more robust effi cacies will be achieved for a wider population of patients. Signifi cance:The clinical benefi t of antiangiogenic drugs is restricted because of intrinsic and acquired limitations. Acknowledging and understanding these limitations will not only allow the development of effective predictive biomarkers but also help in devising new therapeutic strategies that achieve longer effi cacies for a wider population of patients. Cancer Discov; 4(1); 31-41.

SummaryAntiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC) as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX) models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs.

Angiogenesis and metabolism are entwined processes that permit tumor growth and progression. Blood vessel supply is necessary for tumor survival not only by providing oxygen and nutrients for anabolism but also by removing waste products from cellular metabolism. On the other hand, blocking angiogenesis with antiangiogenic therapies shows clinical benefits in treating several tumor types. Nevertheless, resistance to therapy emerges over time. In this review we discuss a novel mechanism of adaptive resistance involving metabolic adaptation of tumor cells, and we also provide examples of tumor adaptation to therapy, which may represent a new mechanism of resistance in several types of cancer. Thus, targeting this metabolic tumor adaptation could be a way to avoid resistance in cancer patients.