Combination treatment using DDX3 and PARP inhibitors induces synthetic lethality in BRCA1-proficient breast cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Triple-negative breast cancers (TNBCs) present poor prognoses due to aggressive nature and limited targeted treatments.
• BRCA1-mutated breast cancers are often TNBCs and exhibit homologous recombination deficiency (HRD), making them sensitive to PARP inhibitors.
• Resistance to PARP inhibitors is frequent in BRCA1-deficient cancers, and sensitivity is limited in BRCA1-proficient cancers.

Purpose of the Study:

• To investigate RNA helicase DDX3 as a therapeutic target in BRCA-proficient and deficient breast cancers.
• To determine if DDX3 inhibition can sensitize breast cancer cells to PARP inhibition.

Main Methods:

• Immunohistochemistry was used to assess DDX3 expression in breast cancer samples from BRCA1 and BRCA2 mutation carriers and sporadic cases.
• Cell viability assays were performed to evaluate sensitivity to the DDX3 inhibitor RK-33 in BRCA-proficient and deficient breast cancer cell lines.
• Combination treatments of RK-33 and the PARP inhibitor olaparib were assessed for synergistic effects.

Main Results:

• High DDX3 expression was observed in 24% of BRCA1 carriers, 21% of BRCA2 carriers, and 30% of sporadic breast cancers.
• BRCA-proficient and deficient breast cancer cell lines showed similar sensitivity to RK-33 (IC50 in low micromolar range).
• Combination therapy with RK-33 and olaparib demonstrated synergy in BRCA1-proficient breast cancer cells (mean combination index 0.59-0.62).

Conclusions:

• Breast cancers, regardless of BRCA proficiency, exhibit similar dependency on DDX3.
• DDX3 inhibition via RK-33 synergizes with PARP inhibitor treatment, offering a potential therapeutic strategy, especially for BRCA1-proficient breast cancers.