Related Experiment Video
Updated: Dec 31, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Low-Dose and Long-Term Olaparib Treatment Sensitizes MDA-MB-231 and SUM1315 Triple-Negative Breast Cancers Spheroids
Clémence Dubois1,2, Fanny Martin3, Chervin Hassel4
1Université Clermont Auvergne, Centre Jean Perrin, INSERM, U1240, Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont Ferrand, France.
Abstract:
The Triple-Negative Breast Cancer subtype (TNBC) is particularly aggressive and heterogeneous. Thus, Poly-ADP-Ribose Polymerase inhibitors were developed to improve the prognosis of patients and treatment protocols are still being evaluated. In this context, we modelized the efficacy of Olaparib (i.e., 5 and 50 µM), combined with fractioned irradiation (i.e., 5 × 2 Gy) on two aggressive TNBC cell lines MDA-MB-231 (BRCAness) and SUM1315 (BRCA1-mutated). In 2D cell culture and for both models, the clonogenicity drop was 95-fold higher after 5 µM Olaparib and 10 Gy irradiation than Olaparib treatment alone and was only 2-fold higher after 50 µM and 10 Gy. Similar responses were obtained on TNBC tumor-like spheroid models after 10 days of co-treatment. Indeed, the ratio of metabolic activity decrease was of 1.2 for SUM1315 and 3.3 for MDA-MB-231 after 5 µM and 10 Gy and of only 0.9 (both models) after 50 µM and 10 Gy. MDA-MB-231, exhibiting a strong proliferation profile and an overexpression of AURKA, was more sensitive to the co-treatment than SUM1315 cell line, with a stem-cell like phenotype. These results suggest that, with the studied models, the potentiation of Olaparib treatment could be reached with low-dose and long-term exposure combined with fractioned irradiation.
Insights
Low-dose Olaparib combined with fractionated irradiation significantly enhances treatment efficacy for aggressive Triple-Negative Breast Cancer (TNBC) models. This combination therapy shows potentiation potential for TNBC patients, suggesting new treatment strategies.
Area of Science:
- Oncology
- Cancer Biology
- Radiotherapy
- Pharmacology
Background:
- Triple-Negative Breast Cancer (TNBC) is an aggressive and heterogeneous subtype requiring improved therapeutic strategies.
- Poly-ADP-Ribose Polymerase (PARP) inhibitors, such as Olaparib, are being evaluated to enhance TNBC treatment outcomes.
- The combination of PARP inhibitors with radiotherapy is a promising approach for managing aggressive cancers.
Purpose of the Study:
- To investigate the efficacy of Olaparib combined with fractionated irradiation on aggressive TNBC cell lines.
- To evaluate the synergistic effects of Olaparib and irradiation on both 2D cell cultures and 3D tumor-like spheroid models.
- To compare the sensitivity of different TNBC models (MDA-MB-231 and SUM1315) to the combined treatment.
Main Methods:
- Modeling the efficacy of Olaparib (5 and 50 µM) combined with fractionated irradiation (5 × 2 Gy) on MDA-MB-231 (BRCAness) and SUM1315 (BRCA1-mutated) TNBC cell lines.
- Assessment of clonogenicity in 2D cell cultures and metabolic activity in 3D tumor-like spheroid models over 10 days of co-treatment.
- Characterization of TNBC cell line phenotypes, including proliferation profiles and AURKA expression.
Main Results:
- A 95-fold higher clonogenicity drop was observed with 5 µM Olaparib and 10 Gy irradiation compared to Olaparib alone in 2D cultures.
- The combination of 5 µM Olaparib and 10 Gy irradiation led to significant metabolic activity decrease (1.2 for SUM1315, 3.3 for MDA-MB-231) in spheroid models.
- MDA-MB-231 cells, with higher proliferation and AURKA expression, showed greater sensitivity to the co-treatment than SUM1315 cells.
Conclusions:
- Low-dose Olaparib combined with fractionated irradiation demonstrates potentiation of anti-cancer effects in aggressive TNBC models.
- The combination therapy is effective in both 2D cultures and 3D tumor-like spheroid models, suggesting clinical relevance.
- These findings suggest that long-term, low-dose Olaparib combined with fractionated irradiation could be a promising strategy for TNBC treatment.
