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

Yongchang Lai,Guohua Zeng,Wenqi Wu,Dong Chen,Zhijian Zhao,Xiongfa Liang,Tao Zeng,Xiaolu Duan

doi:10.1186/s12935-018-0530-2

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel–Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy. VEGF monoclonal antibodies and VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are the main drugs used in anti-angiogenic therapy. However, crosstalk between VEGFR and other tyrosine kinase or downstream pathways produce resistance to TKI treatment, and the multi-target inhibitors, HIF inhibitors or combination strategies are promising strategies for mRCC. HIFs are upstream of the crosstalk between the growth factors, and these factors may regulate the expression of VEGR, EGF, PDGF and other growth factors. The frequent VHL loss in ccRCC increases HIF expression, and HIFs may be an ideal candidate to overcome the TKI resistance. The combination of HIF inhibitors and immune checkpoint inhibitors is also anticipated. Various clinical trials of programmed cell death protein 1 inhibitors are planned. The present study reviews the effects of current and potential TKIs on mRCC, with a focus on VEGF/VEGFR and other targets for mRCC therapy.

Highlights

Renal cell carcinoma (RCC) is the most common kidney solid neoplasm, and 12 drugs are approved in US for metastatic RCC
vascular endothelial growth factor receptor (VEGFR)‐tyrosine kinase inhibitors (TKIs) and other signalling pathways Molecular crosstalk between VEGFR and other tyrosine kinase (TK) or downstream pathways, such as epidermal growth factor receptor (EGFR), c-Met, fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R), c-Kit and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), may have great therapeutic and resistance implications [23, 49]
Cabozantinib is a TKI inhibitor of VEGFR, c-MET and other TKs that exhibited significant clinical benefit in progression-free survival (PFS) and objective response rate over the standard-of-care sunitinib as firstline therapy in patients with intermediate- or poor-risk metastatic RCC (mRCC) [74]

Summary

Introduction

Renal cell carcinoma (RCC) is the most common kidney solid neoplasm, and 12 drugs are approved in US for metastatic RCC (mRCC). More drug combination experiments will be performed with the design and development of less toxic novel immune checkpoint inhibitors and TKIs. VEGFR‐TKIs and other signalling pathways Molecular crosstalk between VEGFR and other TKs or downstream pathways, such as EGFR, c-Met, FGFR, PDGFR, IGF-1R, c-Kit and PI3K/AKT/mTOR, may have great therapeutic and resistance implications [23, 49].

Results

Conclusion