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.

Keywords: drug resistance; metastatic renal cell carcinoma; molecular mechanism; tyrosine kinase inhibitors.

FIGURE 1

Tumor growth patterns associated with vascular co‐option or vascular mimicry. (a) Vascular co‐option. Cancer cells co‐opt pre‐existing mature blood vessels. (b) Vascular mimicry. Cancer cells form a vessel‐like structure.

FIGURE 2

Proposed mechanism of activating bypass pathways in resistance development. TKI treatment initially reduces tumor size. Resistance to tyrosine kinase inhibitors can be mediated by activating bypass pathways. Sphere: tumor cell. Conglomerates of spheres: tumor. TKI, tyrosine kinase inhibitor.

FIGURE 3

Transport of tyrosine kinase inhibitors (TKI) by ABC transporters. (a) TKIs function as a substrate property of ABC transporters. (b) TKIs inhibit the function of ABC transporters. TKIs bind to ATP binding pocket of ABC transporters.

FIGURE 4

The schematic mechanism of lysosomal sequestration. TKI, tyrosine kinase inhibitor.