TP53-altered HCC tumors become addicted to MYC stabilization.
Major finding: TP53-altered HCC tumors become addicted to MYC stabilization.
Mechanism: AURKA binds to and stabilizes phospho-MYC, overcoming G2/M cell-cycle arrest in TP53-altered cells.
Impact: AURKA conformation-changing inhibitors may be beneficial in patients with TP53-altered HCC.
MYC is upregulated in many human tumors and is implicated in tumor initiation and maintenance, but is considered an undruggable target. Thus, strategies to target MYC indirectly are of interest. Proteolytic turnover of the closely related MYCN protein has been shown to be regulated by a kinase-independent function of aurora kinase A (AURKA), and inhibitors that disrupt the native conformation of AURKA can induce MYCN degradation. However, it is not clear if MYC–AURKA complexes exist and could be therapeutically targeted. An in vivo shRNA screen in a mouse model of NrasG12V;Trp53−/− hepatocellular carcinoma (HCC) performed by Dauch and colleagues revealed that Aurka knockdown can override p19ARF-dependent G2/M cell-cycle arrest in hepatocytes, increase tumor development, and reduce overall survival, indicating a tumor-suppressive role of AURKA in this context. However, in the context of chronic liver damage, both AURKA and MYC expression were high in Trp53−/− tumors, and MYC regulated cell-cycle reentry in Trp53−/− hepatocytes. MYC phosphorylation is required for its degradation, and AURKA bound to and stabilized phospho-MYC, overcoming G2/M cell-cycle arrest and promoting tumor cell survival. Alisertib, an AURKA inhibitor in clinical development that induces a conformational change in AURKA, resulted in MYC degradation and increased survival in HCC MYC-overexpressing NrasG12V;Trp53−/− mice, whereas AURKA inhibitors that did not induce a conformational change did not have an effect on Trp53-altered cells. Further, in a human HCC cohort, mutant TP53 was associated with increased mRNA expression of AURKA and of MYC target genes, and treatment of xenografted human TP53-altered HCC cell lines with alisertib resulted in tumor regression, whereas the growth of TP53 wild-type HCC cell line xenografts was not significantly affected. Altogether, these findings suggest that conformation-changing AURKA inhibitors may be used to indirectly target MYC, and indicate that further clinical investigation of AURKA conformation inhibitors may be warranted for the treatment of TP53-altered tumors.
Dauch D, Rudalska R, Cossa G, Nault J-C, Kang T-W, Wuestefeld T, et al. A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med 2016 May 23 [Epub ahead of print].
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