Li Nan, Maly Dustin J, Chanthery Yvan H, Sirkis Daniel W, Nakamura Jean L, Berger Mitchel S, James C David, Shokat Kevan M, Weiss William A, Persson Anders I
Department of Neurology, University of California, San Francisco, California. Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California. Sandler Neurosciences Center, University of California, San Francisco, California.
Department of Chemistry, University of Washington, Seattle, Washington.
Mol Cancer Ther. 2015 Feb;14(2):419-28. doi: 10.1158/1535-7163.MCT-14-0526. Epub 2014 Dec 18.
Glioblastoma (GBM) is the most common malignant primary brain tumor. Radiotherapy fails to eliminate subpopulations of stem-like tumor-propagating cells (TPC), resulting in tumor regrowth. To identify kinases that promote TPC self-renewal rather than increasing proliferation in human GBM cultures, we screened a library of 54 nonselective tool compounds and determined their kinase inhibitor profiles in vitro. Most compounds inhibited aurora kinase (AURK) activity and blocked TPC self-renewal, while inducing GBM cell polynucleation and apoptosis. To prevent regrowth by TPCs, we used a priming dose of radiation followed by incubation with the pan-AURK inhibitor VX680 to block self-renewal and induce apoptosis in GBM cultures. In mice xenografted with human GBM cells, radiotherapy followed by VX680 treatment resulted in reduced tumor growth and increased survival relative to either monotherapy alone or VX680 treatment before radiation. Our results indicate that AURK inhibition, subsequent to radiation, may enhance the efficacy of radiotherapy by targeting radioresistant TPCs in human GBMs.
胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤。放射治疗无法清除肿瘤干细胞样增殖细胞（TPC）亚群，导致肿瘤复发。为了确定促进人类GBM培养物中TPC自我更新而非增加其增殖的激酶，我们筛选了一个包含54种非选择性工具化合物的文库，并在体外确定了它们的激酶抑制剂谱。大多数化合物抑制极光激酶（AURK）活性，阻断TPC自我更新，同时诱导GBM细胞多核化和凋亡。为了防止TPCs导致肿瘤复发，我们采用低剂量放疗，然后与泛AURK抑制剂VX680共同孵育，以阻断GBM培养物中的自我更新并诱导凋亡。在接种了人类GBM细胞的小鼠中，与单独的单一疗法或放疗前的VX680治疗相比，放疗后VX680治疗导致肿瘤生长减缓且生存期延长。我们的结果表明，放疗后抑制AURK可能通过靶向人类GBM中对放疗耐药的TPC来提高放疗效果。
