Dual Targeting of CX3CR1 and PARP in Models of High-Grade Serous Ovarian Carcinoma
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1Department of Pharmaceutical Sciences, College of Pharmacy, The University of Illinois at Chicago, 833 S Wood Str., Chicago, IL 60612, USA.
Background/Objectives:
Clinical use of poly(ADP-ribose) polymerase inhibitors (PARPis) against metastatic high-grade serous ovarian carcinoma (HGSOC) is limited to cases with deficient a homologous recombination (HR). Our objective was to determine whether the impairment of the fractalkine receptor (CX3CR1) could sensitize HR-proficient cases to PARPis.
Methods:
The efficacy of a dual drug combination, including AZD8797, an inhibitor of CX3CR1, and several PARPis was examined using cell lines and xenograft models.
Results:
The effectiveness of PARPis and AZD8797 drug combinations ranged from additive to strongly synergistic. Olaparib was synergistic with AZD8797 in OVCAR-4, Caov-3, and OHSAHO. Niraparib and AZD8797 produced synergy in OVCAR-4 and ES2. Rucaparib and AZD8797 were strongly synergistic in Caov-3 and OVSAHO. Veliparib was strongly synergistic with AZD8797 in OVCAR-4 and Caov-3. Notably, a combination of veliparib and AZD8797 produced a strong synergistic effect in a xenograft model.
Conclusions:
While the exact mechanisms determining the nature of the PARPis and AZD8797 interaction remain to be uncovered, our data indicate that, in a subset of models, selected PARPis strongly synergize with the inhibition of CX3CR1, suggesting a potential therapeutic opportunity.
Insights
Inhibiting the fractalkine receptor (CX3CR1) with AZD8797 can sensitize some ovarian cancer cases to poly(ADP-ribose) polymerase inhibitors (PARPis), offering a new therapeutic strategy for HR-proficient tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Clinical use of PARPis for ovarian cancer is restricted to HR-deficient tumors.
- Homologous recombination (HR) proficiency limits PARPi efficacy in high-grade serous ovarian carcinoma (HGSOC).
Purpose of the Study:
- To investigate if inhibiting CX3CR1 can sensitize HR-proficient HGSOC to PARPis.
- To explore novel therapeutic strategies for ovarian cancer treatment.
Main Methods:
- Tested dual drug combinations of AZD8797 (CX3CR1 inhibitor) and various PARPis.
- Utilized ovarian cancer cell lines and xenograft models for efficacy assessment.
Main Results:
- PARPi and AZD8797 combinations showed additive to synergistic effects.
- Specific synergistic interactions observed between AZD8797 and olaparib, niraparib, rucaparib, and veliparib in different cell lines.
- A veliparib and AZD8797 combination demonstrated strong synergy in a xenograft model.
Conclusions:
- Selected PARPis synergize with CX3CR1 inhibition in a subset of models.
- This combination strategy presents a potential therapeutic opportunity for HR-proficient HGSOC.
- Further research is needed to elucidate the precise interaction mechanisms.
