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Introduction
Renal cell carcinoma (RCC) is the most common kidney cancer subtype. More than 100,000 cases are diagnosed worldwide per year, and RCC accounts for approximately 2–5% of all adult neoplastic diseases and its incidence is rising (1). RCC originates from the tubular structures of the kidney and comprises a heterogeneous group of malignancies. RCC can be classified into four major histological cell types, of which clear cell RCC (ccRCC) is the most common (75–80%) (2). Other types include papillary (10–15%), chromophobe (5%) and collecting duct (1%) RCC. Metastasis may be present at the time of RCC diagnosis and such cases are resistant to radiotherapy, chemotherapy and targeted therapy. Despite great efforts in the field of RCC therapy, RCC remains an incurable disease and the median survival period of patients with advanced RCC is approximately 26 months (3). Therefore, there is a compelling demand to identify both molecular targets and novel drugs with which to treat this disease.
Inhibition of vascular endothelial growth factor (VEGF) receptors is a promising approach for the targeted therapy of RCC. Antiangiogenic drugs for RCC treatment such as sunitinib, pazopanib, sorafenib and axitinib have recently received particular attention (3–5). Sunitinib is a small-molecule inhibitor of multiple receptor tyrosine kinases (RTKs), that inhibits the family of VEGF receptors (VEGFR-1, VEGFR-2 and VEGFR-3), PDGF receptors (PDGFR-α and PDGFR-β), FLT3, the stem cell growth factor receptor KIT and RET. The repressive effect of sunitinib on tumor growth and invasion is mainly achieved by antagonizing the activation of VEGFR and PDGFR, two crucial players in the pathogenesis of RCC. Sunitinib treatment for metastasized RCC contributes to a significantly longer progression-free survival and overall survival. Although sunitinib has become the mainstay of RCC treatment, the occurrence of resistance is a main obstacle overshadowing its clinical benefit. Additional underlying therapeutic targets for RCC include mammalian target of rapamycin (mTOR) kinase, immune checkpoint proteins, indoleamine 2,3-dioxygenase and transforming growth factor-β (3–5).
As tumor cells may escape the inhibition of VEGF signaling using other parallel pathways as growth and survival signals (6), it is necessary to seek accessory pathways to develop new treatment approaches and avoid chemotherapeutic resistance. Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases consisting of 3 isoforms (TrkA, TrkB and TrkC) that are...