Evaluation of the effect of tas-115 inhibitor in modeling of breast cancer lung metastasis

Objective: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking targeted therapies due to the absence of ER, PR, and HER2 expression. TAS-115, a multi-receptor tyrosine kinase inhibitor, blocks autophosphorylation of c-MET/HGF and VEGFR, inhibiting associated signaling pathways such as PI3K/Akt/mTOR, thereby reducing cancer cell survival. No studies to date have evaluated TAS-115's efficacy in TNBC. This study hypothesizes that "Inhibition of the c-MET pathway decreases cancer cells proliferation and migration through downstream pathway modulation." We aim to investigate the effects of TAS-115, both individually and in combination with doxorubicin (DOXO), on the c-MET/HGF and PI3K/Akt/mTOR pathways in a 3D in vitro model. Method: A heterotypic spheroid model was generated using GFP+MDA-MB-231 (TNBC) and NHLF (lung fibroblast) cells. The impact of TAS-115 on spheroids was assessed in a 3D environment, evaluating cell survival, proliferation, and cytokine responses. TAS-115's influence on c-MET/HGF signaling and the downstream PI3K/Akt/mTOR pathway, with emphasis on p-mTOR, was determined. The effects of TAS-115 on spheroid invasion and metastasis potential following 3D bioprinting were also investigated. Results: In the formed heterotypic spheroid model, following the treatment with TAS-115 both individually and in combination with DOXO, a decrease in cancer cell survival and proliferation was observed. Additionally, the expression of c-MET, p-c-MET, and p-mTOR, as well as pro-inflammatory cytokine responses, were significantly reduced. After 3D bioprinting, a marked reduction in the invasion and metastasis potential of the spheroids was also observed (p<0.05). Conclusion: Our study provides critical insights into the effects of TAS-115 on TNBC and lung fibroblast cells in a 3D in vitro environment, evaluating tumor growth, spread, and cytokine responses within the tumor microenvironment. This is the first study to elucidate the c-MET/HGF-mediated effects of TAS-115 in breast cancer, supporting its potential application in TNBC therapy. Keywords: TNBC, c-MET, HGF, TAS-115, 3D bioprinting