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Personalized therapy in renal cell carcinoma: are the different tyrosine kinase inhibitors the same for any patient?

Metastatic renal cell carcinoma (mRCC) is a fatal urological cancer which represents the seventh most common site for tumors, causing more than 140,000 deaths per year worldwide [1]. The past decade has been characterized by the introduction of several targeted agents, such as tyrosine kinase inhibitors (TKIs), directed against several angiogenic drivers of renal cell carcinoma (RCC). These therapeutic agents have radically revolutionized the strategy of treatment and prognosis of patients with mRCC [2–4], increasing progression-free survival and overall survival [5]. The rationale behind this is that tumor survival, growth, and metastasization depend on tumor cells proliferation and angiogenesis, the latter mediated by endothelial cells proliferation. Targeting these processes simultaneously by blocking TKI receptors on tumor cells and vascular endothelial growth factor (VEGF) activity on endothelial cells can be relevant in cancer therapy. Some studies have demonstrated that there is no clear demonstration of superiority between the various molecules of the TKI class [6,7]; there are few published data on the sequential use of two or more TKIs in the treatment of mRCC and most of them are the results of retrospective or phase III studies [8,9], which represent an idealized setting with stringent selection criteria. Yet, 35% of ‘real-life’ patients with mRCC are not eligible for clinical trials for several reasons, the most common being poor performance status and nonclear-cell histology [10]. Different factors, both disease and patient’s characteristics, as well as the peculiar mechanism of action of the drugs, act with synergy and are responsible for the response to a specific treatment. We will go through some of the reasons why in the same patient drugs with similar mechanisms of action produce different disease responses. The first aspect to consider is that RCC is an example of intrinsically heterogeneous tumor, characterized by more variability than other types of cancers, and in which various mutations coexist in different areas of the same tumor, as demonstrated by next-generation sequencing [11]. The heterogeneity is both genetic and epigenetic and remains a major obstacle in the treatment of these patients [12]. Cancer cells are unstable and dynamic cells by definition and therefore they not only distinguish themselves from normal cells but they are also different from each other. So, the pharmacological activity of different drugs could be explained in several ways: tumor cells can have mutations of the site of action of drugs; they can have the ability to decrease the intake, metabolize and eliminate the active drug; they can develop new driver mutations that activate intracellular pathways which favor proliferation, cell growth, and survival. These mutations could eventually overcome the inhibition given by the drugs. All of these points contribute to the peculiar natural history of RCC, which is an ‘unpredictable’ tumor by definition. Secondly, the differences in terms of response and toxicity in patients treated with different drugs of the TKI family may be related to the fact that, being all multikinase inhibitors, each of these drugs acts on a variety of different targets, only partially overlapped by the others. All of them block vascular endothelial growth factor receptor (VEGFR), acting as antiangiogenetic drugs. VEGFR is not the only target of these therapeutic agents; they act on other receptors, blocking their intracellular pathways, such as platelet-derived growth factor receptor (PDGFR)-α and PDGFR-β, cytokine receptor (c-KIT), and others, with a different selectivity [13,14]. For example, sunitinib targets multiple kinase receptors, including VEGFR-1, 2, and 3, PDGFR-α and PDGFR-β, c-KIT, colony-stimulating factor receptor, and neurotrophic factor receptor Rearranged during Transfection gene. Sorafenib inhibits the activity of targets present in the tumor cell (RAF-1 proto-oncogene serine/threonine kinase [CRAF], v-Raf murine sarcoma viral oncogene homolog B1 [BRAF], V600E BRAF, c-KIT, and FMS-like tyrosine kinase 3 [FLT-3]) and in the tumor vasculature (CRAF, VEGFR-2 and 3, and PDGFR-β) [15]. The heterogeneity of the targets of every single drug, the block of intracellular pathways (that can be the driver of proliferation and cell survival), and the different receptor binding affinities of drugs may be the reason why a single patient benefits, in terms of response and survival, from a drug rather than the others. Furthermore, heterogeneity is not only in drug efficacy but also in safety profile. In our everyday experience, we observe that different patients treated with the same drug and at the