Molecular mechanisms of resistance to tyrosine kinase inhibitor in clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC). Loss of von Hippel–Lindau tumor suppressor gene is frequently observed in ccRCC and increases the expression of hypoxia‐inducible factors and their targets, including epidermal growth factor, vascular endothelial growth factor, and platelet‐derived growth factor. Tyrosine kinase inhibitors (TKIs) offer a survival benefit in metastatic renal cell carcinoma (mRCC). Recently, immune checkpoint inhibitors have been introduced in mRCC. Combination therapy with TKIs and immune checkpoint inhibitors significantly improved patient outcomes. Therefore, TKIs still play an essential role in mRCC treatment. However, the clinical utility of TKIs is compromised when primary and acquired resistance are encountered. The mechanism of resistance to TKI is not fully elucidated. Here, we comprehensively reviewed the molecular mechanisms of resistance to TKIs and a potential strategy to overcome this resistance. We outlined the involvement of angiogenesis, non‐angiogenesis, epithelial‐mesenchymal transition, activating bypass pathways, lysosomal sequestration, non‐coding RNAs, epigenetic modifications and tumor microenvironment factors in the resistance to TKIs. Deep insight into the molecular mechanisms of resistance to TKIs will help to better understand the biology of RCC and can ultimately help in the development of more effective therapies.

Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma

“…The process of EMT, which promotes resistance to therapy and metastases, is associated with a host of metabolic changes. Although there are no direct inhibitors to EMT, multiple metabolism-inhibiting drugs have shown indirect activity against EMT changes through various complex biochemical mechanisms [ 105 ] . There are multiple ongoing clinical trials examining the combination of these drugs with antineoplastics agents, although none of these trials include RCC patients [ 106 ] .…”

“…Additionally, TAFs may serve as a target for overcoming resistance. Histone deacetylase inhibitors offer a promising approach to diminish the activation of TAFs and eradicate their infiltration within the tumor stroma, as demonstrated by a study in patients with relapsed or refractory lymphoma or multiple myeloma [ 105 , 107 ] .…”

“…In vitro studies have suggested that combining FGFR inhibitors with other TKIs such as PI3K inhibitors may help mitigate this resistance and inhibit RCC cell metabolic activity [103] . PI3K inhibitors have also demonstrated strong in vitro anti-tumor activity when coadministered with sunitinib [104] .…”

Potentials and future perspectives of multi-target drugs in cancer treatment: the next generation anti-cancer agents

“…Cabozantinib was approved by the FDA for advanced RCC (2016) [ 141 ], HCC (2019) [ 142 ], and differentiated thyroid cancer (2021) [ 143 ]. It provides a substantial clinical advantage over sunitinib when used as the first-line therapy for patients with metastatic RCC [ 144 ]. Additionally, sunitinib-induced resistance can be overcome using cabozantinib in the treatment of RCC [ 145 ].…”

A novel combination therapy with Cabozantinib and Honokiol effectively inhibits c-Met-Nrf2-induced renal tumor growth through increased oxidative stress

“…The receptor tyrosine kinase (RTK), c-Met, is overexpressed and hyper active in both clear cell and papillary RCC [ 2 , 3 ]. Upon binding with the ligand hepatocyte growth factor (HGF), c-Met activates tumor-promoting pathways and can confer therapeutic resistance in RCC [ [4] , [5] , [6] ]. In our previous studies, we found that the induction of c-Met promotes activation of the redox-sensitive transcription factor Nrf2 and over-expression of the cytoprotective molecule heme oxygenase-1 (HO-1).…”