RRC ID 67390
Author Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, Hohmeyer A, Imbeaud S, Yevsa T, Hoenicke L, Pantsar T, Bozko P, Malek NP, Longerich T, Laufer S, Poso A, Zucman-Rossi J, Eilers M, Zender L.
Title A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer.
Journal Nat Med
Abstract 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 p19(ARF). 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.
Volume 22(7)
Pages 744-53
Published 2016-7-1
DOI 10.1038/nm.4107
PII nm.4107
PMID 27213815
MeSH Animals Aurora Kinase A / antagonists & inhibitors Aurora Kinase A / metabolism* Azepines / pharmacology Carcinoma, Hepatocellular / drug therapy Carcinoma, Hepatocellular / genetics* Carcinoma, Hepatocellular / metabolism Cell Cycle Checkpoints Cyclin-Dependent Kinase Inhibitor p16 / genetics Gene Deletion Hepatocytes / metabolism* Humans Liver Neoplasms / drug therapy Liver Neoplasms / genetics* Liver Neoplasms / metabolism Liver Neoplasms, Experimental / drug therapy Liver Neoplasms, Experimental / genetics* Liver Neoplasms, Experimental / metabolism Mice Mice, Knockout Molecular Targeted Therapy Monomeric GTP-Binding Proteins / genetics* Mutation Oncogene Protein p21(ras) / metabolism Phenylurea Compounds / pharmacology Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-myc / metabolism* Pyrimidines / pharmacology RNA, Small Interfering Tumor Suppressor Protein p53 / genetics* Xenograft Model Antitumor Assays
IF 36.13
Resource
Human and Animal Cells HuH-6(RCB1367)