Ifebemtinib and paclitaxel synergistically inhibit the proliferation and metastasis of TNBC by blocking PI3K/Akt pathway through LSD1/PIK3IP1 axis.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy lacking effective therapeutic strategies, resulting in a poor patient prognosis. In this study, we investigated the efficacy and underlying molecular mechanisms of the combination of FAK inhibitor Ifebemtinib and paclitaxel in TNBC. We found that FAK were significantly upregulated in breast cancer and correlated with poor prognosis in both breast cancer and TNBC patients. In vitro, the combination of Ifebemtinib and paclitaxel synergistically suppressed proliferation and colony-formation of TNBC cells. Through inactivating CDK1, they induced cell cycle arrest at G2/M phase. By down-regulating Bcl-2 and up-regulating Bax, the combination induced triggered apoptosis. By up-regulating E-cadherin, down-regulating N-cadherin and vimentin, they inhibited migration of TNBC cells. In vivo, the combination inhibited TNBC cell proliferation and spontaneous lung metastasis. Mechanistically, on one hand, the combination synergistically inhibited phosphorylation-mediated activation of FAK. On the other hand, they downregulated LSD1, thereby relieving LSD1-mediated transcriptional repression of PIK3IP1, which is a negative regulator of the PI3K/Akt pathway, leading to accumulation of PIK3IP1. By inhibiting FAK activation and upregulating PIK3IP1, Ifebemtinib and paclitaxel blocked the PI3K/Akt pathway, effectively suppressing TNBC proliferation and metastasis. Our findings suggest that FAK may serve as a potential therapeutic target for TNBC.