Unexpected effects of a selective and potent c-MET inhibitor in an immunocompetent intraductal model for triple-negative breast cancer

Tumor growth and dissemination are often driven by stimulatory signaling pathways that can be targeted to reduce disease progression. The c-MET pathway represents such a typical treatment candidate, but till date most c-MET inhibitors are either not effective and/or selective against aggressive cancers such as triple-negative breast cancer (TNBC). A novel selective and potent c-MET inhibitor OMO-1 was preclinically evaluated for its efficacy in combination with and without cisplatin chemotherapy in an innovative mouse model for TNBC. After 4T1 triple-negative mammary tumor cells were injected intraductally in lactating mammary glands of syngeneic BALB/c mice, they recapitulated the complete TNBC process from ductal carcinoma in situ (DCIS) to invasive carcinoma (IC) and subsequent metastasis. Systemic treatment was started once tumor cells underwent ductal epithelial breakthrough (i.e. DCIS to IC transition), mirroring clinical indications in TNBC patients. Although 4T1 primary tumor growth did not rely on c-MET signaling, the daily oral administration of OMO-1 resulted in decreased tumor growth and provided additional tumor and metastasis reduction in combination with cisplatin. At the stromal level, OMO-1 stimulated an anti-tumorigenic microenvironment by increasing immune activation in primary tumors. Importantly, OMO-1 treatment reduced tumor hypoxia by stimulating vessel normalization as indicated by the increased expression of pericyte markers (alpha-smooth muscle actin, platelet-derived growth factor receptor-β and angiopoietin-1). In turn, these matured vessels facilitated enhanced delivery of cisplatin to the primary tumors and subsequent tumor cell death. Our partially unexpected data now warrant translation of this candidate OMO-1 therapy from a preclinical setting to TNBC patients.

Publication year:2021