Steenbrugge Jonas, Vander Elst Niels, Demeyere Kristel, De Wever Olivier, Sanders Niek N, Van Den Broeck Wim, Ciamporcero Eric, Perera Timothy, Meyer Evelyne
Laboratory of Biochemistry, Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
NPJ Breast Cancer. 2021 Mar 17;7(1):27. doi: 10.1038/s41523-021-00234-8.
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.
c-MET被认为是癌症进展的驱动因素，影响肿瘤生长和肿瘤支持性基质。在此，我们研究了强效选择性c-MET抑制剂OMO-1在具有免疫活性的三阴性乳腺癌（TNBC）导管内小鼠模型中的治疗效果。OMO-1作为单一疗法剂量依赖性地降低了非c-MET成瘾的4T1肿瘤进展，并与顺铂联合使用进一步减少了疾病。在基质水平上，OMO-1显著减少了4T1肿瘤中的中性粒细胞浸润，促进了免疫激活，并增强了顺铂介导的肿瘤相关巨噬细胞的减少。OMO-1治疗还减少了4T1肿瘤的缺氧并增加了周细胞标志物的表达，这表明血管成熟。与此发现一致，OMO-1治疗后顺铂向4T1原发性肿瘤的递送增强，增加了顺铂DNA加合物水平和肿瘤细胞死亡。尽管需要在其他细胞系中进行验证，但我们的发现提供了初步证据，表明TNBC患者可能从OMO-1治疗中受益，即使在非c-MET成瘾肿瘤的情况下也是如此。
