How anti-angiogenic drugs are able to induce resistance to their own therapeutic effect in human metastatic renal carcinoma

Anti-angiogenic drugs have proven to be efficient in most types of cancers, but secondary resistance is constantly observed, and mechanisms of resistance remain poorly understood in patients. In studies on human samples of renal cell carcinoma, our team recently demonstrated that sunitinib, a tyrosine kinase inhibitor, was able to generate resistance to its own therapeutic effect in cancer stem cells via induced hypoxia. This review highlights the main perspectives for innovative therapeutic strategies to overcome acquired resistance to anti-angiogenic drugs: i) Should we adjust our protocols on the basis of the moment of onset of necrosis in the tumor? ii) Using hyperoxia to decrease the number of cancer stem-cells in the resistant metastasis and resensitize the tumor could be another innovative therapeutic perspective. iii) Why not directly target cancer stem-cells? Although many questions remain, the results of our study support cancer stem-cell evaluation in biopsies of patients treated with sunitinib, and further research on the role of hypoxia in tumors resistant to anti-angiogenic drugs.