Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewResistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives
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.
Section snippets
Up-regulation of proangiogenic pathways
An established cause for the development of resistance to VEGF-targeted therapy is tumor hypoxia. Tumors exceeding a volume of 1 mm3 usually contain regions of hypoxia [15]. It is well known that tumor hypoxia is associated with increased invasiveness and metastasis, and poorer patient survival [15], [16]. Targeting tumor angiogenesis, e.g. by blocking VEGF signaling, leads to increased hypoxia in the tumor which in turn leads to necrosis and decrease of tumor burden. However, hypoxia also leads
Potential predictive biomarkers of response and resistance to sunitinib
As described above, a subgroup of RCC patients is intrinsically resistant to, or develops acquired resistance upon, treatment with sunitinib. (Bio)markers accurately identifying these patients will help managing this disease more optimally.
Conclusions and future perspectives
Although different mechanisms of resistance have been identified such as up-regulation of proangiogenic pathways, recruitment of BMDCs, promotion of tumor invasiveness and metastasis, and activation of alternative signaling pathways, one factor seems to play a crucial role in all these processes: tumor hypoxia. Targeting the tumor vasculature with VEGF-targeted agents renders the tumor cells hypoxic with subsequent accumulation of HIF1, which in turn leads to up-regulation of proangiogenic
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2021, Pharmacological ResearchCitation Excerpt :NS-398, an inhibitor of HIF-2α/COX-2 pathway, can reverse hypoxia induced sorafenib resistance in RCC [58]. Furthermore, a series of preclinical and clinical data have also confirmed that HAPs, which cause DNA damage only under extreme hypoxic conditions, have a good application prospect in the treatment of RCC patients who are resistant to sorafenib therapy [16,64]. Meanwhile, nutlin-3, an inhibitor of MDM2-p53 interaction, can synergistically enhance the antitumor efficacy of sorafenib by inhibiting the ubiquitin degradation of p53 and activating the p53-regulated apoptotic pathway [65].
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