Design of combination therapeutics from protein response to drugs in ovarian cancer cells

Area of Science:

• Oncology
• Proteomics
• Pharmacology

Background:

• High-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic cancer, necessitating new therapeutic strategies.
• Understanding cellular responses to drug perturbations is crucial for designing effective combination therapies.

Purpose of the Study:

• To identify potential drug combinations for overcoming resistance in HGSOC using proteomic profiling.
• To evaluate the anti-proliferative effects of novel drug combinations and single agents in HGSOC cell lines.

Main Methods:

• Unbiased quantitative protein mass spectrometry was employed to analyze cellular responses to drug perturbations.
• Network analysis identified drug-specific protein responses and potential resistance markers.
• Experimental testing of 12 drug combinations and GPX4 inhibitors in six HGSOC cell lines.

Main Results:

• Proteomic profiling revealed proteins associated with general drug resistance and drug-specific responses.
• Network analysis identified novel markers for resistance, guiding the design of anti-resistance drug pairs.
• Several drug combinations demonstrated synergistic or additive anti-proliferative effects, including with PARPi, MEKi, and SRCi.
• GPX4 inhibitors showed significant single-agent activity (0.05-0.11 µM) in the OVCAR-4 cell line.

Conclusions:

• Proposed drug combinations represent potential therapeutic candidates for ovarian cancer treatment.
• GPX4 inhibitors show promise as single agents for ovarian cancer therapy.
• These findings offer novel strategies to overcome or prevent drug resistance in HGSOC.