Editors' ChoiceCancer

Targeting AURKA to drug the undruggable

Sci. Signal.  02 Aug 2016:
Vol. 9, Issue 439, pp. ec175
DOI: 10.1126/scisignal.aah6669

The growth of various cancers is driven by increased activity of RAS family enzymes or increased abundance of the transcription factor MYC. Some hepatocellular carcinomas (HCCs) exhibit both abnormalities in conjunction with mutations in p53, a transcription factor that promotes cell cycle arrest and apoptosis. However, these HCCs lack targeted therapeutic options because RAS and MYC are largely considered “undruggable.” Dauch et al. have found a druggable target—surprisingly, a tumor suppressor—that partners with MYC and enables its activity in p53-mutant liver cancer. An RNA interference screen combined with deep sequencing in tumors from genetic mouse models of hepatocarcinoma suggested that the growth of NRAS-driven, p53-mutant liver cancer cells depended on a high abundance of MYC and the mitosis checkpoint kinase aurora kinase A (AURKA). However, various experiments in transgenic mice indicated that AURKA was a tumor suppressor and that expression of the gene encoding it was induced by RAS-mediated activation of the cyclin-dependent kinase inhibitor 2A (CDKN2A, also known as p19ARF), which also promotes p53 stability. In HCC cells lacking wild-type p53, phosphorylated (but not unphosphorylated) MYC immunoprecipitated with AURKA. The phosphorylation of MYC promotes its ubiquitylation and proteasome-mediated degradation. Treating cells with allosteric inhibitors of AURKA kinase activity (MLN8237 and CD532) prevented the formation of new AURKA-phosphorylated MYC complexes, induced the degradation of MYC, and led to cell death. Injecting MLN8237 into mice bearing HCC xenografts that were NRAS-positive and either p53-mutant or p53-null suppressed tumor growth and improved animal survival. Increased AURKA expression correlated with that of mutant TP53 (the gene that encodes p53) and of MYC in human HCCs. The findings suggest that interaction with AURKA stabilizes MYC, which promotes cell cycling in the absence of functional p53. Therefore, conformational AURKA inhibitors that block this interaction may be a way to treat patients with MYC-positive, NRAS-driven, p53-mutant liver cancer.

D. Dauch, R. Rudalska, G. Cossa, J.-C. Nault, T.-W. Kang, T. Wuestefeld, A. Hohmeyer, S. Imbeaud, T. Yevsa, L. Hoenicke, T. Pantsar, P. Bozko, N. P. Malek, T. Longerich, S. Laufer, A. Poso, J. Zucman-Rossi, M. Eilers, L. Zender, A MYC–aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat. Med. 22, 744–753 (2016). [PubMed]