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Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma
Jie Bao1, Sanna Pikkusaari1, Jun Dai1
1Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.
Abstract:
Ovarian high-grade serous cancer (HGSC) is the most aggressive ovarian cancer subtype with limited treatment options. We identify the PDPK1 inhibitor BX-912 as a promising candidate, showing strong single-agent activity and synergy with the PARP inhibitor olaparib, independent of BRCA status. Unexpectedly, BX-912 induces multinucleation, a phenotype not seen with other PDPK1 inhibitors. Proteome Integral Solubility Alteration (PISA) assay reveals HES1 as a functional off-target, while structural modeling suggested BX-912 acts as a protein-protein interaction modulator, driving nuclear accumulation of HES1 complexes and hence inducing mitotic catastrophe. Cell-cycle analyses confirm enhanced DNA damage response and G2/M arrest when combined with olaparib. These findings uncover a novel mechanism for BX-912, establish HES1 inhibition as a therapeutic strategy in HGSC, demonstrate proteomics' power to reveal hidden drug activities, and propose sequential cell-cycle targeting to improve treatment efficacy.
Insights
The PDPK1 inhibitor BX-912 shows promise against ovarian high-grade serous cancer (HGSC), working alone or with olaparib. It uniquely causes multinucleation by affecting HES1, leading to mitotic catastrophe and enhanced DNA damage.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Ovarian high-grade serous cancer (HGSC) is an aggressive subtype with limited therapeutic strategies.
- Current treatments often face resistance, necessitating novel therapeutic approaches.
Purpose of the Study:
- To identify novel therapeutic targets and agents for HGSC.
- To investigate the mechanism of action of the PDPK1 inhibitor BX-912 in HGSC.
- To evaluate the synergistic potential of BX-912 with PARP inhibitors.
Main Methods:
- Screening of PDPK1 inhibitors for anti-cancer activity in HGSC models.
- Proteome Integral Solubility Alteration (PISA) assay to identify off-target interactions.
- Structural modeling to elucidate drug-target engagement.
- Cell-cycle analysis and DNA damage assays to assess drug effects.
- Combination studies with olaparib, a PARP inhibitor.
Main Results:
- BX-912 demonstrated significant single-agent activity and synergistic effects with olaparib in HGSC, irrespective of BRCA mutation status.
- BX-912 uniquely induced multinucleation, a phenotype linked to HES1 as a functional off-target.
- The drug acts as a protein-protein interaction modulator, causing nuclear accumulation of HES1 complexes and mitotic catastrophe.
- Combination therapy enhanced DNA damage response and induced G2/M cell-cycle arrest.
Conclusions:
- BX-912 represents a promising therapeutic candidate for HGSC, with a novel mechanism involving HES1 inhibition.
- Targeting HES1 offers a potential therapeutic strategy for HGSC.
- Proteomics can uncover unexpected drug activities and mechanisms.
- Sequential cell-cycle targeting may improve treatment efficacy in HGSC.
