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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• MYC oncoproteins are crucial in human tumor development but are considered undruggable.
• Mutations in the tumor suppressor p53 (TP53) are common in many cancers, including hepatocellular carcinoma (HCC).
• NRAS-driven cancers with TP53 mutations exhibit addiction to MYC stabilization.

Purpose of the Study:

• To investigate the mechanism of MYC stabilization in TP53-deficient, NRAS-driven liver cancer.
• To identify potential therapeutic targets for this specific cancer subgroup.
• To evaluate the efficacy of Aurora Kinase A (AURKA) inhibitors.

Main Methods:

• Direct in vivo shRNA screening in mouse models.
• Analysis of protein-protein interactions between MYC and AURKA.
• Treatment with conformation-changing AURKA inhibitors in preclinical models.
• Assessment of AURKA and MYC expression in human HCC samples.

Main Results:

• TP53-mutated, NRAS-driven liver cancer cells rely on AURKA-mediated MYC stabilization to bypass cell cycle arrest.
• MYC directly binds to AURKA; inhibiting this interaction leads to MYC degradation and cancer cell death.
• Conformation-changing AURKA inhibitors suppressed tumor growth and improved survival in relevant mouse models.
• Human TP53-mutated HCCs show elevated AURKA expression and a positive correlation with MYC levels.
• Human HCC xenografts with TP53 mutations or deletions were highly sensitive to AURKA inhibitors.

Conclusions:

• Targeting the MYC-AURKA interaction with specific inhibitors offers a promising therapeutic strategy for TP53-mutated HCC.
• AURKA inhibitors represent a potential treatment for a subset of human liver cancers.
• This study identifies a novel therapeutic vulnerability in MYC-driven cancers with TP53 alterations.