Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives

Highlights

• Sunitinib resistance in renal cell carcinoma appears to be transient and reversible.

• Tumor hypoxia plays a crucial role in several resistance mechanisms.

• Hypoxia-mediated cMET signaling leads to an increased malignant potential.

• Targeting cMET seems to be the most promising pharmacological treatment option.

• DNA promoter hypermethylation could represent promising predictive factors.

Abstract

The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC.

Introduction

Renal cell carcinoma (RCC), which arises from the renal parenchyma, is the most common kidney cancer subtype, accounting for approximately 90% of all cases [1], [2]. Of the patients diagnosed with RCC, 20–30% present with metastasized disease, and another ~ 30% of the patients treated for localized disease develop metastases during follow-up [3]. RCC is not a single entity, but comprises a heterogeneous group of malignancies, of which clear cell RCC (ccRCC) is the most common (75–80%) and the best studied to date. ccRCCs are highly vascularized tumors that are characterized by frequent inactivation (50–75%) of the Von Hippel–Lindau (VHL) gene [2], [4], [5]. The product of the VHL gene, pVHL, plays an important role in down-regulating the expression of the hypoxia inducible factor 1 (HIF1) transcription factor, which leads to decreased angiogenesis (Fig. 1). Inactivation of pVHL, e.g. by mutation, deletion or promoter CpG island methylation of the VHL gene, leads to accumulation of HIF1 and increased transcription of HIF1 target genes e.g. vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The frequent inactivation of VHL provided the rationale for the development of antiangiogenic drugs to treat ccRCC such as sunitinib, pazopanib, sorafenib, and axitinib [4]. Sunitinib is an oral multiple tyrosine kinases inhibitor (TKI), that inhibits the family of vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2 and VEGFR-3), the platelet-derived growth factor receptors (PDGFRα and PDGFRβ), FLT3, cKIT and RET. The inhibitory effect of sunitinib on tumor angiogenesis is mainly achieved by blocking VEGFR and PDGFR, two key players in the pathogenesis of ccRCC [6], [7]. In metastasized ccRCC, sunitinib treatment resulted in a significant longer progression free survival (PFS) (11 versus 5 months, P < 0.001) and overall survival (OS) (26.4 versus 21.8 months, P = 0.049) compared to treatment with interferon alpha (IFN-α) [8], and it has therefore become the mainstay of treatment.

Initial response rates to sunitinib lie between 30% and 40% [9], [10], [11]. However, disease progression usually occurs after a median of 6–15 months [12], indicating the existence of intrinsic (primary) and/or acquired (secondary) resistance. The resistance mechanisms to sunitinib can be divided in several distinct groups, namely up-regulation of proangiogenic signaling pathways, resistance mediated by the tumor microenvironment, increased tumor invasiveness and metastasis, activation of alternative signaling pathways, inadequate target inhibition, and resistance mediated by the action of microRNAs (Fig. 2). More recently, it was shown that pazopanib has similar efficacy as sunitinib, but with a favorable safety and toxicity profile [13], [14]. As a result, sunitinib and pazopanib are used interchangeably in clinical practice. It is likely that the potential resistance mechanisms that are identified for sunitinib may also account for pazopanib, since they have the same molecular targets. However, to the best of our knowledge, no literature on resistance to pazopanib has yet been published. Therefore, the focus of this review will be on sunitinib resistance. We will discuss data from preclinical and clinical studies on mechanisms of sunitinib resistance, and summarize the current knowledge on potential predictive markers that can help to select patients that are likely to benefit from treatment with sunitinib. Finally, we will discuss future perspectives on how to optimize the treatment of patients with metastasized RCC.