Highlights of This Issue

Abstract

Aurora kinases regulate multiple aspects of mitosis and cell division and represent therapeutic targets for cancer treatment. In this study, Farrell and colleagues describe the novel investigational multitargeted Aurora B kinase inhibitor TAK-901 that shows timedependent, tight-binding inhibition of Aurora B. Although TAK-901 inhibited multiple kinases in biochemical assays, it potently inhibited only a few other kinases in intact cells. TAK-901 displayed the hallmarks of Aurora B inhibition in cellular and xenograft tumor models and showed potent antitumor effects in multiple xenograft models. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase 1 clinical trials.Monoclonal antibodies against mesothelin are being evaluated for the treatment of mesothelioma and other cancers and show great promise for clinical development for solid cancers. The present study generated SD1, a human single-domain antibody recognizing the C-terminal end (residues 539–588) of mesothelin close to the cell surface. SD1 exhibited strong complement-dependent cytotoxicity, in addition to antibody-dependent cell-mediated cytotoxicity, against mesothelin-expressing tumor cells. Furthermore, the new antibody caused growth inhibition of human tumor xenografts in mice as a single agent. SD1 shows potential as a novel cancer therapeutic candidate and may improve current antibody therapy targeting mesothelin-expressing tumors.The reason(s) for the poor response to chemotherapy in some triple-negative breast cancer (TNBC) patients is still unclear. Yin and colleagues found that treatment of TNBC cells with cisplatin and TRAIL results in a significant increase in apoptosis and upregulation of FZD8, one of the Wnt receptors, and its downstream targets LEF1 and TCF in surviving cells. The authors also found that treatment of mice bearing CRL2335 tumors with cisplatin and TRAIL mostly depleted non-tumor-initiating cells (non-TICs), resulting in residual tumors enriched in TICs with increased FZD8 expression. These findings suggest a novel molecular mechanism to explain the drug resistance commonly found in TNBC patients.Erlotinib and gefitinib are both EGFR inhibitors with similar but not identical chemical structure used for the treatment of NSCLC. In order to determine whether differences seen in clinical outcomes can be attributed to their protein interaction profiles, a chemical proteomics study was done. Contrary to gefinitib, erlotinib displaced the ternary complex formed by ILK, α-parvin, and PINCH, which is involved in epithelial to mesenchymal transition. Based on structural, cellular, and clinical observations, Augustin and colleagues propose that the binding of erlotinib to this complex results in slowing down the metastatic process and that it may be important in EGFR wild-type disease.