Combination of Proteasome and Histone Deacetylase Inhibitors Overcomes the Impact of Gain-of-Function p53 Mutations

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• TP53 mutations are prevalent in solid tumors, with gain-of-function (GOF) mutations conferring oncogenic properties and poor prognosis.
• Identifying therapeutic strategies against GOF TP53 mutants is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To discover novel therapeutic targets for overcoming the detrimental effects of GOF TP53 mutations.
• To evaluate the efficacy of proteasome inhibitors and histone deacetylase inhibitors (HDACi) in gynecologic cancer cell lines with specific GOF TP53 mutations.

Main Methods:

• Utilized gynecologic cancer cell lines with characterized TP53 mutational status.
• Administered proteasome inhibitors and HDAC inhibitors, assessing their impact on cell viability and apoptosis.
• Investigated the molecular mechanisms, including the unfolded protein response and p53 protein levels.

Main Results:

• Proteasome inhibitor treatment induced cell death in cancer cells harboring recurrent GOF TP53 mutations (R175H, R248Q).
• The addition of HDAC inhibitors potentiated the anti-cancer effects of proteasome inhibitors.
• p53-null cancer cells demonstrated relative resistance to the combination therapy, suggesting a TP53-dependent mechanism.

Conclusions:

• The combination of proteasome inhibitors and HDAC inhibitors shows promise for targeting cancers with GOF TP53 mutations.
• Proteasome inhibition may induce apoptosis via the unfolded protein response in GOF TP53 mutant cells.
• Further clinical studies are warranted to validate these findings in a preselected patient population with GOF TP53 mutations.