Antiangiogenic Tyrosine Kinase Inhibitors Have Differential Efficacy in Clear Cell Renal Cell Carcinoma in Bone

Authors

Stefan Maksimovic
Nina C Boscolo
Ludovica La Posta
Sergio Barrios
Mohammad Jad Moussa
Emanuela Gentile
Pedro I Pesquera
Wenjiao Li
Jianfeng Chen
Javier A Gomez
Akshay Basi
Jared K Burks
Christopher Alvarez-Breckenridge
Jianjun Gao
Matthew T Campbell
Eleonora Dondossola

Publication Date

10-1-2024

Journal

Cancer Research Communications

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35% to 40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel-Lindau protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, antiangiogenic tyrosine kinase inhibitors (TKI) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared their anticancer efficacy, impact on mouse survival, and mechanisms of action, including effects on tumor cells and both immune and nonimmune (blood vessels and osteoclasts) bone stromal components. This approach elucidates the efficacy of TKIs in ccRCC bone tumors to support rational interrogation and development of therapies.

Significance: TKIs showed different efficacy in synchronous bone and lung metastases and did not eradicate tumors as single agents but induced extensive reprogramming of the BM microenvironment. This resulted in a significant decrease in neoangiogenic blood vessels, bone remodeling, and immune cell infiltration (including CD8 T cells) with altered spatial distribution.

Keywords

Carcinoma, Renal Cell, Bone Neoplasms, Kidney Neoplasms, Animals, Humans, Mice, Angiogenesis Inhibitors, Protein Kinase Inhibitors, Neovascularization, Pathologic, Lung Neoplasms, Tumor Microenvironment, Cell Line, Tumor, Xenograft Model Antitumor Assays, Female, Tyrosine Kinase Inhibitors

DOI

10.1158/2767-9764.CRC-24-0304

PMID

39248577

PMCID

PMC11459607

PubMedCentral® Posted Date

10-8-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes