Research programme 04
Restoring cell-cycle control in oncogene-driven cancers
We test whether reactivating DREAM or destabilizing oncogenic proteins can expose selective vulnerabilities in HPV-associated and TP53-mutant cancers.
Central question
Can tumors that disable RB-family control be forced back into a repressive cell-cycle state or selectively eliminated through their dependence on oncogenic protein stability?
High-risk HPV E7 proteins neutralize RB-family tumor suppressors and disrupt DREAM, enabling persistent cell-cycle gene expression. Structure-guided strengthening of the LIN52–p130 interaction can partially restore DREAM assembly in HPV-positive cells and suppress proliferation, providing proof of principle that a disabled repressor complex can be functionally re-engaged.
A complementary translational programme examines mutant p53 in non-small-cell lung cancer. Recent work showed that proteasome inhibition can paradoxically promote degradation of the gain-of-function p53 R273H protein through an Hsp70-associated mechanism, suggesting a potential vulnerability in selected TP53-mutant tumors.
Approaches
- HPV-positive cellular models
- Structure-guided protein engineering
- Isogenic TP53 models
- Proteasome-inhibitor studies
- Co-immunoprecipitation and protein-stability assays
- Flow-cytometric apoptosis analysis
Selected work
- Proteasome inhibition paradoxically degrades gain-of-function mutant p53 R273H in NSCLC and could have therapeutic implications (2024)
- Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells (2021)
- Structural mechanisms of DREAM complex assembly and regulation (2015)