Aurora激酶B抑制增强三阴性乳腺癌的放射应答并激活1型干扰素信号通路

Purpose: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies and poor response to radiotherapy 1 . Aurora kinase B (AURKB), a key regulator of chromosomal segregation during mitosis, is overexpressed in TNBC and correlates with poor recurrence-free survival following radiation 2 . Because radiation-induced DNA damage can promote innate immune activation through type I interferon (T1IFN) signaling 3 , we hypothesized that AURKB inhibition would enhance radiosensitivity while amplifying T1IFN-mediated antitumor immune responses in TNBC. Methods: AURKB expression was analyzed across breast cancer datasets and correlated with clinical outcomes. Pharmacologic inhibition of AURKB using ATP-competitive (barasertib-HQPA) and noncompetitive (SP-96) compounds was evaluated in multiple human and murine TNBC cell lines. Clonogenic survival assays quantified radiosensitization, and DNA damage was assessed by gammaH2AX and micronuclei formation. Type I interferon (T1IFN) activation was measured using IFN-beta reporter assays, quantitative PCR for CXCL10 and PD-L1, and flow cytometry for surface MHC-I and PD-L1 expression. In vivo efficacy of AURKB inhibition combined with radiotherapy was evaluated in syngeneic TNBC models. Results: AURKB expression was significantly elevated in TNBC and associated with poor outcomes in radiotherapy-treated patients. AURKB inhibition enhanced radiosensitivity in TNBC cell lines in vitro and reduced tumor growth in vivo. Combined AURKB inhibition and radiation increased micronuclei formation, consistent with genomic instability and cytosolic DNA accumulation. This combination also induced a robust T1IFN response, evidenced by increased reporter activity, upregulation of CXCL10 and PD-L1 transcripts, and elevated MHC-I and PD-L1 expression. These effects were observed following both single-dose and fractionated radiation regimens. Conclusions: AURKB inhibition potentiates the efficacy of radiotherapy in TNBC by augmenting DNA damage and activating antitumoral T1IFN signaling. These findings identify AURKB as a dual radiosensitizing and immune-stimulatory target in TNBC, providing a strong rationale for clinical evaluation of AURKB inhibitors in combination with radiotherapy. References: 1. Chandler BC, Moubadder L, Ritter CL, Liu M, Cameron M, Wilder-Romans K, et al. TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination. J Clin Invest. 2020;130(2):958-73. 2. Chang HHY, Pannunzio NR, Adachi N, Lieber MR. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 2017;18(8):495-506. 3. Fuertes MB, Woo S-R, Burnett B, Fu Y-X, Gajewski TF. Type I interferon response and innate immune sensing of cancer. Trends in immunology . 2013;34(2):67-73.