Abstract
Several therapeutic options are available for metastatic RCC, but responses are almost never complete, and resistance to therapy develops in the vast majority of patients. Consequently, novel treatments are needed to combat resistance to current therapies and to improve patient outcomes. We have applied integrated transcriptome and proteome analyses to identify cathepsin B (CTSB), a cysteine proteinase of the papain family, as one of the most highly upregulated gene products in established human RCC xenograft models of resistance to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). We used established RCC models to test the significance of CTSB in the progression of renal cancer. Our evaluation of CTSB showed that stable CTSB knockdown suppressed RCC growth in vitro and in vivo. Stable over-overexpression of wild-type CTSB (CTSBwt/hi), but not of an CTSB active site mutant (CTSBN298A), rescued cell growth in CTSB knockdown cells and abolished the efficacy of VEGFR TKI treatment. Genome-wide transcriptome profiling of CTSB knockdown cells demonstrated significant effects on multiple metabolic and stem cell-related pathways, with ALDHA1A (ALDH1) as one of the most significantly downregulated genes. Importantly, survival analysis across 16 major TCGA cancers revealed that CTSB overexpression is associated with low rates of three and five year patient survival rates (P = 2.5e–08, HR = 1.4). These data strongly support a contribution of CTSB activity to RCC cell growth and tumorigenicity. They further highlight the promise of CTSB inhibition in development of novel combination therapies designed to improve efficacy of current TKI treatments of metastatic RCC.
Highlights
Many patients with metastatic renal cell carcinoma (RCC) benefit from treatment with tyrosine kinase inhibitors (TKIs) such as sunitinib, axitinib, and pazopanib, Chen et al Oncogenesis (2019)8:15Page 2 of 18 15 advances, patients continue to experience clinical disease progression, and physicians lack the ability to augment TKI responses in patients who have developed resistance to prior vascular endothelial growth factor receptor (VEGFR) therapy
TKI resistance in murine xenografts. These Von Hippel-Lindau (VHL)-deficient human RCC xenografts initially respond to VEGFR TKI treatment with reduced tumor growth rates
To identify candidate protein markers linked to sunitinib resistance in RCC, we performed quantitative proteome profiling on xenograft tumors obtained under three conditions: treatment-naive mice (“untreated”), tumors briefly exposed to sunitinib (“responding” or “Day 3”), and tumors harvested at the time of sunitinib resistance (~Day 30–40)
Summary
Many patients with metastatic renal cell carcinoma (RCC) benefit from treatment with tyrosine kinase inhibitors (TKIs) such as sunitinib, axitinib, and pazopanib, Chen et al Oncogenesis (2019)8:15Page 2 of 18 15 advances, patients continue to experience clinical disease progression, and physicians lack the ability to augment TKI responses in patients who have developed resistance to prior VEGFR therapy. We have previously demonstrated the utility for treatment of metastatic mRCC of simultaneous targeting of proteins controlling distinct phases of angiogenesis, such as ALK-1 and VEGFR; this combination therapy results in regression of advanced tumors by downregulating multiple genes from the Notch signaling pathway[3]. Building on these results, we have developed mouse RCC models of TKI resistance and performed genomewide transcriptome and proteome analyses to better understand the mechanisms of resistance, as well as to identify their underlying key genetic drivers. Bussolati and colleagues recently showed that clones of CD105 + tumor/progenitor cells from human renal carcinomas can maintain hemostasis and differentiate into tumor endothelium and epithelium, both in vitro and in vivo[8,10]
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