AXL kinase inhibitor exhibits antitumor activity by inducing apoptotic cell death in triple-negative breast cancer cells

초록

Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with a poor prognosis and decreased patient survival. It is intimately linked to AXL overexpression and AXL hyperactivation. Here, we explored the therapeutic potential of AX-0085, a small molecule AXL inhibitor. While AX-0085 was previously characterized in the context of lung adenocarcinoma, this study demonstrates its application in triple-negative breast cancer (TNBC) models. AX-0085 exhibited high binding affinity to the ATP binding site located beneath the conserved glycine-rich loop (P-loop) that links the β1 and β2 strands of the AXL kinase domain. Furthermore, it was demonstrated that the benzamide group of AX-0085 and LyS567's Nζ atom could generate a hydrogen bond. AX-0085 efficiently suppressed the AXL/GAS6 signaling pathway activation in TNBC cells in vitro, which in turn prevented AXL/GAS6 signaling-dependent pro-cancerous behavior like cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT). In TNBC, an AX-0085-induced cell cycle arrest that took place during the G1 phase reduced the expression of CYCLIN E and CDK2. Additionally, AX-0085 facilitated apoptotic cell death in TNBC. Treatment of AX-0085 on in vivo mouse xenografts transplanted with 4 T1 cells showed a significant tumor reduction. Thus, our findings demonstrate that AX-0085 has an effective therapeutic role in TNBC by inhibiting AXL activation.

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