Vascular Endothelial Growth Factor Receptor (VEGFR) Tyrosine Kinase Inhibitor (TKI) Resistance in Metastatic Renal Cell Carcinoma (mRCC): Possible Mechanisms and Clinical Approaches

Introduction

The availability of six new agents for the treatment of metastatic renal cell carcinoma (mRCC) in the last 5 years has dramatically changed the therapeutic landscape for this disease. The vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) sorafenib,1–3 sunitinib,4, 5 and pazopanib6; the monoclonal antibody against vascular endothelial growth factor (VEGF) bevacizumab7–10; and the inhibitors of the mammalian target of rapamycin (mTOR) pathway temsirolimus11 and everolimus12, 13 are all approved by the US Food and Drug Administration. Compared with prior cytokine therapies, the new therapies targeting angiogenesis and other signal transduction pathways appear to have both increased clinical activity, as measured by objective responses, reduction in tumor burden, and prolongation of progression-free survival, as well as better toxicity profiles. In addition, they likely have broader applicability to the general mRCC patient population. Although the important advances in treatment of mRCC were the direct result of a better understanding of its biology, the rapid development of multiple new agents has outstripped our ability to understand the exact molecular mechanisms by which resistance to these agents occurs.

Abstract

INTRODUCTION

The approvals of sorafenib, sunitinib, and pazopanib have led to increased options for patients with mRCC. Unfortunately, some patients treated with these vascular endothelial growth factor receptor (VEGFR) TKI progress rapidly, while the majority of remaining patients will develop evidence of disease progression within 2 years.

OBJECTIVES

We gathered preclinical and clinical evidence regarding potential mechanisms of VEGFR TKI resistance and clinical approaches to counter it.

METHODS

We searched the published medical literature, searching the National Library of Medicine (PubMed) as well as abstracts from annual meetings of the American Society of Clinical Oncology (ASCO) and American Association for Cancer Research (AACR).

RESULTS

No clear evidence-based mechanism of VEGFR TKI resistance has been defined to date; therefore, we summarize the existing hypothesis-generating preclinical, biomarker, and clinical data. Potential mechanisms of resistance to VEGFR TKI include variations in the inherent genetic alterations associated with RCC, independent of VHL. In addition, response to hypoxia induced by VEGFR TKI may drive alternative growth factor mediated angiogenesis. Molecular imaging evidence of early angiogenesis and proliferation rebound following VEGFR TKI exposure suggests progression is still driven by a proangiogenic phenotype.

CONCLUSION

By necessity, clinicians must currently make treatment decisions on the basis of limited data regarding the biology of VEGFR TKI resistance. RCC is a heterogeneous disease from the onset. Understanding the specific genetic profiles of sensitive and resistant subtypes of RCC may aid in both first-line and subsequent treatment selection. In addition, better understanding of tumor response and resistance may lead to novel combination strategies in the future.

Keywords

vascular endothelial growth factor receptor (VEGFR), tyrosine kinase inhibitor (TKI), renal cell carcinoma (RCC), mechanisms of resistance, genetic, molecular imaging