Crosstalk between VEGFR and other receptor tyrosine kinases for TKI therapy of metastatic renal cell carcinoma

TKIs treatments are associated with dynamic changes in relevant biomarkers, including other protein TKs [27]. For example, VEGFR-TKI treatment significantly reduced vessel density (CD31) and phospho-S6K, PD-L1, and FOXP3 expression and significantly increased Ki-67, cytoplasmic FGF-2 and MET receptor expression in vessels [27]. However, long-lasting efficacy is seldom achieved, and evasive resistance eventually occurs under anti-angiogenic TKI therapy [28]. A recent study suggested that long non-coding RNAs (lncRNAs) play a significant role in TKI resistance in RCC. lncRNA-SRLR may be resistant to sorafenib and serve as a predictive biomarker for sorafenib tolerance via directly binding to NF-κB and the promotion of IL-6 transcription, which leads to STAT3 activation [29].

Exosomes also play a key role in resistance to drug theraphy. Stromal cells orchestrate an intricate crosstalk with tumour cells via utilization of exosomes to expand therapy resistance and reinitiate tumour growth [30]. lncARSR may promote and disseminate sunitinib resistance via competitively binding to miR-34/miR-449 to facilitate AXL and c-MET expression, incorporating into exosomes and transmitting to sensitive in RCC cells [31]. MiR-21 and miR-126 are targets of lncRNAs, and these molecules may be probable prognostic markers and therapeutic targets in RCC [32].

Various multi-targeted TKIs were developed because resistance to TKI treatment is inevitable. Sorafenib is a multi-targeted TKI that significantly improved clinical outcomes of mRCC patients [33]. However, no significant differences between sorafenib and sunitinib were observed in the treatment of advanced renal cancer in Chinese patients [34]. Axitinib, bevacizumab, and pazopanib are also anti-angiogenic drugs that approved for use in mRCC. Interleukin (IL)-8 expression is elevated, during sunitinib resistance, which suggests that IL-8 is also an key contributor and a potential therapeutic target to reverse sunitinib resistance in ccRCC [35]. Patients with high concentrations of IL-8, osteopontin and HGF exhibited shorter progression-free survival (PFS) compared to patients with low IL-8 concentrations using pazopanib as a treatment drug [36]. Cabozantinib is an important new standard-of-care treatment option for patients with advanced RCC who previously received anti-angiogenic therapy [37, 38]. VEGF is the downstream target of the HIF signal, and drugs that inhibit HIF-2 are in various stages of clinical testing [5]. The targeting of angiogenesis and hypoxia pathways may provide a resolution for the anti-angiogenesis resistance [28]. The HIF2α antagonist PT2385 is a novel therapeutics for RCC, and it exhibited cogent preclinical efficacy and improved tolerability [39]. Table 3 shows the factors, genes, proteins and other molecules (e.g., P-gp, MRP, and GSTs) involved in TKI resistance.

The development of TKIs is revolutionary progress, but TKIs exhibit side effects, including cardiovascular side effects, especially hypertension and congestive heart failure, and continual clinical monitoring should be emphasized in the use of new TKI agents [40, 41]. Cardiac damage from TKIs (sorafenib and sunitinib) treatment is a largely underrated phenomenon, but it is manageable with careful cardiovascular monitoring and cardiac treatment at the first signs of myocardial damage [42]. Another TKIs, cabozantinib, also exhibited a manageable adverse events profile in patients with advanced RCC [37]. Sunitinib increases buccodental toxicity compared to chemotherapy [43].

Immunotherapy enjoyed tremendous development recently in the form of immune checkpoint inhibition and vaccines [44]. VEGF-A/VEGFR-2 is also related to with tumour escape. VEGF-A directly triggers Treg proliferation, and VEGF-A/VEGFR-2 blockade inhibits this effect. Therefore, anti-VEGF-A therapies may also exert immunological effects [45]. A combination of immunotherapy treatment is also in process [46]. The combination of an IL-6 inhibitors (tocilizumab) and TKIs (sorafenib) may be a novel therapeutic approach for RCC [47]. Anti-VEGF (bevacizumab) in combination with an anti-PD-L1 (atezolizumab) improved antigen-specific T cell migration in mRCC [48]. More drug combination experiments will be performed with the design and development of less toxic novel immune checkpoint inhibitors and TKIs.

The mTOR/Raptor complex (mTORC1) is a key molecule in the PI3K/AKT/mTOR signalling pathway, and its activation increases protein synthesis and cell survival via direct phosphorylation of its effectors. Inhibitors of mTOR, such as everolimus and temsirolimus, are approved for the treatment of mRCC. Administration of everolimus alone or with lenvatinib is one of the most effective options for mRCC [50]. However, the inhibition of mTORC1 produces a loss of negative feedback loops, which upregulates the downstream effectors of the PI3K/AKT/mTOR pathway and activates of HIFs (an activator of angiogenesis) [51].

A combination of agents targeting the multiple pathways of angiogenesis, including HIF, VEGFR, PI3K and mTORC1/2, will likely be a beneficial choice. Lenvatinib plus everolimus and lenvatinib alone improved PFS in patients with mRCC who progressed after administration of one previous VEGF-targeted therapy [52]. The combination of bevacizumab and temsirolimus in patients previously treated with VEGFR-TKI is possible, but with dose reductions and treatment discontinuations [53]. The antidiabetic drug metformin blocks cell growth via TORC1 inhibition, and the combination of metformin and VEGF-TKI may be effective [54]. Combined treatment with everolimus and a Toll-like receptor 9 agonist immune modulatory oligonucleotide effectively interfered with tumour growth and angiogenesis in VHL wild-type and mutant models of RCC [55].