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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Multiomics profiling and experiments in preclinical models revealed RAD51-IN-1 as a synergistic potentiator of
Huangyang Meng1,2, Qianjing Chang1,2, Yashuang Zhang1,2
1Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, Nanjing, 210029, China.
Abstract:
Anlotinib has demonstrated preliminary efficacy as a first-line maintenance therapy for ovarian cancer. However, clinical responses vary widely. To investigate resistance mechanisms and explore rational combinations, pretreatment tumors from 18 patients in clinical trial NCT04807166 underwent whole-exome and RNA sequencing and stratified into sensitive and resistant groups based on progression-free survival. VEGFR-related mutations were enriched in sensitive tumors, whereas resistant tumors showed increased activity of DNA repair pathways and Notch signaling. In vitro screening identified strong synergy between anlotinib and the RAD51 inhibitor RAD51-IN-1, which outperformed the Notch inhibitor FLI-06 in resistant patient-derived organoids. Mechanistic studies revealed that RAD51 inhibition was associated with impaired HRR and increased sensitivity to anlotinib. In vivo, combined treatment with anlotinib and RAD51-IN-1 significantly reduced tumor burden without notable toxicity. These findings suggest that RAD51-mediated HRR may contribute to anlotinib resistance and support RAD51 inhibition as a promising approach to overcome therapeutic resistance in ovarian cancer.
Insights
Anlotinib shows promise for ovarian cancer maintenance therapy, but resistance occurs. Targeting RAD51-mediated DNA repair with RAD51-IN-1 combined with anlotinib overcomes resistance, significantly reducing tumors with minimal toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anlotinib is a potential first-line maintenance therapy for ovarian cancer.
- Clinical responses to anlotinib vary, necessitating investigation into resistance mechanisms.
Purpose of the Study:
- To investigate anlotinib resistance mechanisms in ovarian cancer.
- To identify rational combination therapies to overcome anlotinib resistance.
Main Methods:
- Whole-exome and RNA sequencing of pretreatment tumors from 18 ovarian cancer patients (NCT04807166).
- Stratification of patients into sensitive and resistant groups based on progression-free survival.
- In vitro screening of drug combinations and in vivo validation in mouse models.
Main Results:
- Sensitive tumors showed enriched VEGFR-related mutations.
- Resistant tumors exhibited increased DNA repair and Notch signaling activity.
- Combined anlotinib and RAD51 inhibitor RAD51-IN-1 demonstrated synergy, impairing homologous recombination repair (HRR) and enhancing anlotinib sensitivity.
Conclusions:
- RAD51-mediated HRR contributes to anlotinib resistance in ovarian cancer.
- RAD51 inhibition is a promising strategy to overcome anlotinib resistance.
- Combination therapy with anlotinib and RAD51-IN-1 warrants further clinical investigation.
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