期刊
JOURNAL OF CLINICAL MEDICINE
卷 9, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/jcm9010064
关键词
Triple-Negative Breast Cancer; SUM1315; MDA-MB-231; PARPi Olaparib; fractioned radiotherapy; co-treatment; the three-dimensional cell culture; spheroid; transcriptomic analysis
资金
- Ligue Contre le Cancer grant, under the project name PINKMIND
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 mu M), combined with fractioned irradiation (i.e., 5 x 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 mu M Olaparib and 10 Gy irradiation than Olaparib treatment alone and was only 2-fold higher after 50 mu M 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 mu M and 10 Gy and of only 0.9 (both models) after 50 mu M 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.
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