Data for this Review were identified by a search of the National Library of Medicine (PubMed) by use of the search terms: “renal-cell carcinoma,” “renal carcinoma” or “kidney cancer”, and “targeted therapy” with further limits defined as adult human studies and core clinical journals in English. Only papers published since 1980 were considered. 472 articles were retrieved. We then further refined this list by excluding review articles that did not directly address resistance. We also
ReviewResistance to targeted therapy in renal-cell carcinoma
Introduction
Renal-cell carcinoma (RCC) is a disease characterised by highly vascular tumours (figure 1). Therapy targeted at the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways now represents the standard of care in metastatic RCC. Each of these approaches offers significant clinical benefit, as measured by objective responses, reduction in tumour burden, and prolongation of progression-free or overall survival compared with previous therapeutic standards. However, complete or durable responses have been only rarely noted, necessitating chronic therapy for most patients. Furthermore, treatment has typically been associated with the development of resistance after a median of 6–15 months of treatment. Sequential use of these agents has become the empirical standard of care, with activity seen even when using an agent with a similar target after disease progression on a previous therapy. Thus, a pressing clinical and scientific question arises about the mechanism(s) of resistance to VEGF-targeted and mTOR-targeted therapy, and the optimum treatment approach for patients with metastatic RCC in this setting. Emerging clinical and preclinical data are available to address this issue. In this Review, we summarise the existing data that provide insight into this issue, and discuss methodological issues for drug investigation in this setting.
Section snippets
Mechanism of action of existing therapy
The pathogenesis of RCC identifies the VEGF and mTOR pathways as relevant therapeutic targets. RCC is characterised by inactivation of a crucial tumour-suppressor gene, known as von Hippel Lindau (VHL).1, 2 VHL encodes the VHL protein, which is a component of an E3 ubiquitin–ligase complex that targets a transcription factor, hypoxia-inducible factor (HIF), for proteasome-mediated degradation (figure 2). If VHL is inactivated, a defective VHL protein is produced and HIF is not degraded.
Insights into mechanisms of resistance
Although in some malignant diseases (eg, lung cancer and chronic myeloid leukaemia) the development of resistance to a targeted therapy (eg, erlotinib or imatinib) is often due to a mutation in a gene encoding a key receptor tyrosine kinase targeted by the drug,17, 18, 19, 20 this mechanism seems to be an unlikely explanation for the development of resistance to VEGF-pathway antagonists. Because the main target for VEGFR inhibitors resides on endothelial cells, a mutation conferring treatment
Clinical definition of resistance
In view of the fact that many treatment options for metastatic RCC now exist, it is important to not only maximise current therapy, but also to realise when the treatment benefit has ended so that subsequent therapy can be considered. Resistance to or failure of antiangiogenic agents is currently defined by the evidence of disease progression according to RECIST criteria despite therapy. This progression is defined as an increase of 20% or more in the sum of measurable lesions, the appearance
Investigative strategies for overcoming resistance
Several strategies emerge from the above considerations regarding resistance mechanisms to currently available therapeutics in RCC. The first involves the use of an agent that blocks a resistance mechanism. Such an agent could be used as monotherapy at the time of resistance to targeted therapy, could be added to continued VEGF blockade at the time of resistance, or could be added initially in combination with VEGF blockade with the hope of delaying the onset of resistance. Alternatively, more
Conclusions
Despite the reliance of renal carcinoma cells and surrounding stroma on elements of the VEGF and mTOR pathways, the inability to sustain initial tumour stabilisation or regression induced by VEGF-pathway or mTOR-pathway blockade is a significant clinical issue. Existing evidence suggests that resistance to VEGF blockade is related to re-establishment of angiogenesis, but does not provide a clear and unique mechanism. Clinical data showing efficacy of dose increases or alternate (probably more
Search strategy and selection criteria
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