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Updated: Aug 16, 2026
Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
AXL targeting by a specific small molecule or monoclonal antibody inhibits renal cell carcinoma progression in an
Tony J Chen1, Piotr Mydel2,3, Małgorzata Benedyk-Machaczka3
1Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Abstract:
AXL tyrosine kinase activation enhances cancer cell survival, migration, invasiveness, and promotes drug resistance. AXL overexpression is typically detected in a high percentage of renal cell carcinomas (RCCs) and is strongly associated with poor prognosis. Therefore, AXL inhibition represents an attractive treatment option in these cancers. In this preclinical study, we investigated the antitumor role of a highly selective small molecule AXL inhibitor bemcentinib (BGB324, BerGenBio), and a newly developed humanized anti-AXL monoclonal function blocking antibody tilvestamab, (BGB149, BerGenBio), in vitro and an orthotopic RCC mice model. The 786-0-Luc human RCC cells showed high AXL expression. Both bemcentinib and tilvestamab significantly inhibited AXL activation induced by Gas6 stimulation in vitro. Furthermore, tilvestamab inhibited the downstream AKT phosphorylation in these cells. The 786-0-Luc human RCC cells generated tumors with high Ki67 and vimentin expression upon orthotopic implantation in athymic BALB/c nude mice. Most importantly, both bemcentinib and tilvestamab inhibited the progression of tumors induced by the orthotopically implanted 786-0 RCC cells. Remarkably, their in vivo antitumor effectiveness was not significantly enhanced by concomitant administration of a multi-target tyrosine kinase inhibitor. Bemcentinib and tilvestamab qualify as compounds of potentially high clinical interest in AXL overexpressing RCC.
Insights
AXL inhibitors bemcentinib and tilvestamab show promise for treating renal cell carcinoma (RCC). These agents effectively reduced tumor growth in preclinical models, highlighting their potential in AXL-overexpressing cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- AXL tyrosine kinase signaling is crucial for cancer cell survival, migration, invasion, and drug resistance.
- AXL overexpression is prevalent in renal cell carcinoma (RCC) and correlates with poor patient prognosis.
- Targeting AXL presents a potential therapeutic strategy for RCC treatment.
Purpose of the Study:
- To evaluate the preclinical antitumor efficacy of bemcentinib (a small molecule AXL inhibitor) and tilvestamab (a monoclonal antibody AXL inhibitor) in RCC.
- To assess the in vitro and in vivo effects of these agents on AXL-driven signaling pathways and tumor progression.
Main Methods:
- In vitro assessment of bemcentinib and tilvestamab on AXL activation and downstream signaling (AKT phosphorylation) in 786-0-Luc RCC cells stimulated with Gas6.
- Establishment of an orthotopic RCC mouse model using 786-0-Luc cells characterized by high AXL, Ki67, and vimentin expression.
- Evaluation of the in vivo antitumor efficacy of bemcentinib and tilvestamab, both as single agents and in combination with a multi-target tyrosine kinase inhibitor.
Main Results:
- Both bemcentinib and tilvestamab effectively inhibited Gas6-induced AXL activation in vitro.
- Tilvestamab demonstrated inhibition of downstream AKT phosphorylation in RCC cells.
- In vivo, both bemcentinib and tilvestamab significantly suppressed tumor progression in the orthotopic RCC mouse model.
- Combination therapy with a multi-target tyrosine kinase inhibitor did not significantly enhance the antitumor effects of bemcentinib or tilvestamab.
Conclusions:
- Bemcentinib and tilvestamab exhibit significant preclinical antitumor activity in an orthotopic RCC model.
- These AXL inhibitors are promising candidates for further clinical investigation in AXL-overexpressing RCC.
- The findings support the therapeutic potential of targeting AXL in renal cell carcinoma.
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