OMO-1 reduces progression and enhances cisplatin efficacy in a 4T1-based non-c-MET addicted intraductal mouse model for triple-negative breast cancer

Jonas Steenbrugge,Olivier De Wever,Eric Ciamporcero,Evelyne Meyer,Niels Vander Elst,Kristel Demeyere,Niek N Sanders,Timothy Perera,Wim Van Den Broeck

doi:10.1038/s41523-021-00234-8

Jonas Steenbrugge, Olivier De Wever + Show 7 more

Open Access

https://doi.org/10.1038/s41523-021-00234-8

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Abstract

c-MET is considered a driver of cancer progression, impacting tumor growth and tumor-supporting stroma. Here, we investigated the therapeutic efficacy of OMO-1, a potent and selective c-MET inhibitor, in an immunocompetent intraductal mouse model for triple-negative breast cancer (TNBC). OMO-1 reduced non-c-MET addicted 4T1 tumor progression dose dependently as monotherapeutic and provided additional disease reduction in combination with cisplatin. At the stromal level, OMO-1 significantly reduced neutrophil infiltration in 4T1 tumors, promoted immune activation, and enhanced cisplatin-mediated reduction of tumor-associated macrophages. OMO-1 treatment also reduced 4T1 tumor hypoxia and increased expression of pericyte markers, indicative for vascular maturation. Corroborating this finding, cisplatin delivery to the 4T1 primary tumor was enhanced upon OMO-1 treatment, increasing cisplatin DNA-adduct levels and tumor cell death. Although verification in additional cell lines is warranted, our findings provide initial evidence that TNBC patients may benefit from OMO-1 treatment, even in cases of non-c-MET addicted tumors.

Highlights

IntroductionBound by hepatocyte growth factor (HGF), the receptor tyrosine kinase c-MET provides necessary survival and migration signals during embryogenesis[2,3,4]
The c-MET pathway is known to drive cellular malignant processes and has been reported as a target for anticancer therapy[1,2,3,4].Bound by hepatocyte growth factor (HGF), the receptor tyrosine kinase c-MET provides necessary survival and migration signals during embryogenesis[2,3,4]
One strategy to tackle cancer is by inhibiting pathways that increase tumor cell survival, proliferation, and migration such as the HGF/c-MET pathway, which is currently being investigated in multiple cancer types[1,2,3,4]

Summary

Introduction

Bound by hepatocyte growth factor (HGF), the receptor tyrosine kinase c-MET provides necessary survival and migration signals during embryogenesis[2,3,4]. Whilst mutations in this pathway stimulate the growth and metastasis of some tumors, it plays a major role in the tumor stroma. In the context of triple-negative breast cancer (TNBC), c-MET is overexpressed in about 52% of TNBC patient tumors, and high c-MET expression is correlated with worse disease-free as well as overall survival[7,8] These findings have prompted the clinical testing of c-MET signaling blockers for TNBC, including ATP-competitive small molecule inhibitors[1]

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