Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma

Patrick L Sweeney; Yash Suri; Arnab Basu; Vadim S Koshkin; Arpita Desai

doi:10.20517/cdr.2023.89

Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma

Cancer Drug Resist. 2023 Dec 28;6(4):858-873. doi: 10.20517/cdr.2023.89. eCollection 2023.

Authors

Patrick L Sweeney¹, Yash Suri², Arnab Basu³, Vadim S Koshkin⁴, Arpita Desai⁴

Affiliations

¹ Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
² University of Arizona College of Medicine, Tucson, AZ 85724, USA.
³ Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA.
⁴ Division of Hematology and Oncology, Department of Medicine, University of California at San Francisco School of Medicine, San Francisco, CA 94143, USA.

Abstract

Renal cell carcinoma (RCC), the most prevalent type of kidney cancer, is a significant cause of cancer morbidity and mortality worldwide. Antiangiogenic tyrosine kinase inhibitors (TKIs), in combination with immune checkpoint inhibitors (ICIs), are among the first-line treatment options for patients with advanced RCC. These therapies target the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase pathway and other kinases crucial to cancer proliferation, survival, and metastasis. TKIs have yielded substantial improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced RCC. However, nearly all patients eventually progress on these drugs as resistance develops. This review provides an overview of TKI resistance in RCC and explores different mechanisms of resistance, including upregulation of alternative proangiogenic pathways, epithelial-mesenchymal transition (EMT), decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration, alterations in the tumor microenvironment including bone marrow-derived cells (BMDCs) and tumor-associated fibroblasts (TAFs), and genetic factors such as single nucleotide polymorphisms (SNPs). A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKI resistance, thereby improving outcomes for patients with advanced RCC.

Keywords: Antiangiogenic tyrosine kinase inhibitors; acquired resistance; immune checkpoint inhibitors; renal cell carcinoma; sunitinib; tumor microenvironment.

Publication types

Review