FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Area of Science:

• Molecular Biology
• Cancer Research
• DNA Repair Mechanisms

Background:

• Flap Endonuclease 1 (FEN1) is crucial for DNA repair pathways including long patch base excision repair (LP-BER) and Okazaki fragment maturation.
• FEN1 overexpression in patients correlates with aggressive ovarian cancer phenotypes and reduced survival after platinum chemotherapy.

Purpose of the Study:

• To investigate the therapeutic potential of targeting FEN1 in ovarian cancer, particularly in platinum-resistant cases.
• To explore the mechanisms underlying FEN1's role in chemoresistance and identify potential synthetic lethal interactions.

Main Methods:

• Analysis of a clinical cohort for FEN1 expression and patient outcomes.
• Pre-clinical studies involving cisplatin treatment, FEN1 depletion, gene inactivation, and inhibition in ovarian cancer cell lines.
• Generation and characterization of FEN1 inhibitor-resistant cell lines (PEO1R) to study resistance mechanisms.
• High-throughput screening of compounds to identify novel FEN1 inhibitors.

Main Results:

• FEN1 overexpression is linked to poor progression-free survival in ovarian cancer patients treated with platinum chemotherapy.
• FEN1 inhibition or depletion resensitizes platinum-resistant ovarian cancer cells to cisplatin.
• BRCA2-deficient cells show synthetic lethality upon treatment with a FEN1 inhibitor.
• FEN1 inhibitor-resistant cells (PEO1R) exhibit restored BRCA2 function and altered expression of POLβ and XRCC1.
• FEN1 inhibition selectively targets POLβ-deficient ovarian cancer cells.

Conclusions:

• FEN1 is a validated therapeutic target for ovarian cancer, especially for overcoming platinum resistance.
• Targeting FEN1 offers a potential strategy for synthetic lethality in BRCA2-deficient ovarian cancers.
• Novel FEN1 inhibitors have been identified through high-throughput screening, paving the way for drug development.