東芬蘭大學的研究人員和蒂賓根大學的研究人員發現了一個新的分子機製，該分子機製可用於抑製肝細胞癌的生長，這是一種最常見的肝癌。這項研究結果發表在《Nature Medicine》雜誌上。

　　通過研究發現，小鼠和人類肝癌的功能蛋白質p53蛋白通過極光激酶(AURKA)和MYC蛋白質之間的交互作用而被幹擾或抑製。用特定的藥物分子幹擾AURKA蛋白來抑製這種交互作用，最終導致肝癌細胞死亡。

　　借助計算機輔助分子模型的作用， 東芬蘭大學製藥和藥物化學研究小組分析了AURKA蛋白質和MYC蛋白質之間的相互作用。這種分子模型也會幫助人們理解為什麼隻有某些藥物分子可以抑製AURKA蛋白質和MYC蛋白質之間的交互作用，而其它藥物對它們則沒有影響。此外，該分子模型可預測某種藥物分子是否可以抑製AURKA蛋白質和MYC蛋白質之間的交互作用。

　　MYC癌基因蛋白保護絕大多數人類腫瘤，一直被人們認為無藥可治的。通過體內 shRNA的直接篩選，我們的研究發現在腫瘤抑製基因編碼蛋白p53(小鼠TrP53和人類Trp53)中肝癌細胞產生了突變。

　　目前，還沒有有效的藥物可治療晚期肝癌。通過專門靶向研究AURKA蛋白質，可以有效防止p53的生長從而抑製肝癌發展。這項研究的發現可以用在這種癌症患者治療的發展方向上。

　　針對這種靶向治療肝癌的新方法， 東芬蘭大學和蒂賓根大學啟動了新抗癌藥物發展的項目。德國和法國的幾所大學和研究機構也參與了這項研究。

　　doi:10.1038/nm.4107

　　PMC:

　　PMID:

　　A MYC–aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer

　　Daniel Dauch, Ramona Rudalska, Giacomo Cossa, Jean-Charles Nault, Tae-Won Kang, Torsten Wuestefeld, Anja Hohmeyer, Sandrine Imbeaud, Tetyana Yevsa, Lisa Hoenicke, Tatu Pantsar, Przemyslaw Bozko, Nisar P Malek, Thomas Longerich, Stefan Laufer, Antti Poso, Jessica Zucman-Rossi, Martin Eilers &Lars Zender

　　MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19ARF. MYC directly binds to AURKA, and inhibition of this protein–protein interaction by conformation-changing AURKA inhibitors results in subsequent MYC degradation and cell death. These conformation-changing AURKA inhibitors, with one of them currently being tested in early clinical trials, suppressed tumor growth and prolonged survival in mice bearing Trp53-deficient, NRAS-driven MYC-expressing hepatocellular carcinomas (HCCs). TP53-mutated human HCCs revealed increased AURKA expression and a positive correlation between AURKA and MYC expression. In xenograft models, mice bearing TP53-mutated or TP53-deleted human HCCs were hypersensitive to treatment with conformation-changing AURKA inhibitors, thus suggesting a therapeutic strategy for this subgroup of human HCCs.