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Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that poses a clinical challenge. Thus, new therapy strategies are urgently needed. The selective WEE1 inhibitor, AZD1775, has shown strong anti-proliferative effects on a variety of tumors. Here, we first demonstrate that inhibition of ATR by selective inhibitor AZD6738 can enhance AZD1775-caused growth inhibition in TNBC. Our results show that the enhanced cell death is attributed to repressed DNA damage repair and excessive replication stress, thereby causing increased DNA damage reflected by accumulation of the DNA double-strand-break marker γH2AX. On the other hand, combined treatment with AZD6738 and AZD1775 forces mitotic entry of cells with DNA damages by activating CDK1 activity, inducing severely aberrant mitosis and mitotic catastrophe, ultimately resulting in cell death. Dual inhibition of WEE1 and ATR also inactivated RAD51-mediated homologous recombination, which sensitized TNBC cells to cisplatin and PARP inhibitor. Here, based on the preclinical results that ATR inhibition synergizes with WEE1 inhibition in TNBC, we propose that this combination therapy alone, or in parallel with chemotherapy, represents an innovative and potent targeted therapy in TNBC.

In response to the wide spread of microbial contamination induced by bacterial pathogens, the development of novel materials with excellent antibacterial activity is of great interest. In this study, novel antibacterial chitosan (CS) and polyhexamethylene guanidine hydrochloride (PHGC) dual-polymer-functionalized graphene oxide (GO) (GO-CS-PHGC) composites were designed and easily fabricated. The as-prepared materials were characterized by Fourier transform infrared (FTIR), X-ray photoelectron spectrometer (XPS), field emission scanning electron microscopy (FE-SEM), transmission electron microscope (TEM), thermogravimetric analysis (TGA) and Raman spectroscopy. Their antibacterial capability towards bacterial strains was also studied by incubating both Gram-negative bacteria and Gram-positive bacteria in their presence. More significantly, the synergistic antibacterial action of the three components was assayed, and the findings implied that the as-prepared GO-CS-PHGC shows enhanced antibacterial activity when compared to its single components (GO, CS, PHGC or CS-PHGC) and the mixture of individual components. Not only Gram-negative bacteria but also Gram-positive bacteria are greatly inhibited by GO-CS-PHGC composites. The minimum inhibitory concentration (MIC) value of GO-CS-PHGC against E. coli was 32 μg/mL. With the powerful antibacterial activity as well as its low cost and facile preparation, GO-CS-PHGC has potential applications as a novel antibacterial agent in a wide range of biomedical uses.