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. 2024 Feb;44(2):282-286.
doi: 10.1002/cac2.12509. Epub 2023 Dec 15.

Enhancing sensitivity of triple-negative breast cancer to DNA-damaging therapy through chemical inhibition of the m6A methyltransferase METTL3

Bianca Cesaro  1 , Alessia Iaiza  2 , Fabio Piscopo  2 , Marco Tarullo  2 , Eleonora Cesari  3 , Dante Rotili  4 , Antonello Mai  4   5 , Alberto Diana  6 , Michela Londero  6 , Luca Del Giacco  6 , Riccardo Masetti  3   7 , Alba Di Leone  3   7 , Chiara Naro  3   8 , Silvia Masciarelli  1 , Giulia Fontemaggi  9 , Claudio Sette  3   8 , Francesco Fazi  1   5 , Alessandro Fatica  2
Affiliations

Enhancing sensitivity of triple-negative breast cancer to DNA-damaging therapy through chemical inhibition of the m6A methyltransferase METTL3

Bianca Cesaro et al. Cancer Commun (Lond). 2024 Feb.
No abstract available

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
STM2457 inhibitor affects proliferation, viability, and metastatic potential of TNBC and synergizes with olaparib and platinum‐salt. (A) Growth curve (left panel) and MTT assay (central and right panels) of MDA‐MB‐231 and MCF‐10A cell lines treated with different concentrations of STM2457 (1, 5, 10, 20, 40, 100 μmol/L) or DMSO. (B) Cell colony formation assay of MDA‐MB‐231 and MCF‐10A cell lines treated with 5 μmol/L STM2457 (STM). Representative images from three experimental replicates are shown; the histograms represent the mean of colonies percentage ± SD, n = 3. (C) Wound healing assay to evaluate the migration ability of MDA‐MB‐231 cells treated with 20 μmol/L STM2457; the histogram represents the mean of migration percentage ± SD, n = 3. (D) MTT assay of MDA‐MB‐231 cells treated with 10 μmol/L STM, 10 μmol/L cisplatin or combination of both drugs for 72 h. (E) The histogram represents the percentage of apoptotic cells (mean ± SD) treated as in (D). (F) MTT assay of MDA‐MB‐231 cells treated with 10 μmol/L STM, 20 μmol/L olaparib or combination of both drugs for 72 h. (G) The histogram represents the percentage of apoptotic cells (mean ± SD) treated as in (F). (H) 48 hpf zebrafish embryos were directly engrafted into the PVS with MDA‐MB‐231 GFP‐positive cells. Upper panel, representative fluorescence stereomicroscope images of the CHT region, containing the extravasated GFP‐positive cells 24 hpi, which display the 4 discrete classes categorizing the xenotransplants (high, medium, low, absent). Lateral view, anterior to the left. Lower panel, evaluation of cells ability to extravasate through 48 hpf zebrafish embryos xenograft. Each bar represents the mean value % of larvae at 24 hpi calculated from, at least, two independent experiments. Total number of embryos analyzed was 213, divided as follows: DMSO (n = 28), STM (n = 45), cisplatin (n = 37), cisplatin + STM (n = 53), olaparib (n = 26), olaparib + STM (n = 24). (I) Representative bright‐field images of BCO‐21; lower panel shows hematoxylin‐eosin staining. (J) Cytotoxic effects of STM2457 on BCO‐21. Cells were exposed to various concentrations of the drugs for 5 days and viability was evaluated by Cell Titer Glo 3D assay. (K) Synergistic effects of STM2457 and carboplatin or olaparib on BCO viability. BCO‐21 was exposed for 5 days to combined treatments with suboptimal (5 μmol/L) and optimal (10 μmol/L) doses of STM, carboplatin (10 μmol/L) and olaparib (10 μmol/L). CI values < 1, indicating synergism, were calculated for drug combinations in comparison to individual drugs and are displayed above the graphs. All results are expressed as the mean ± SEM derived from triplicates. *P < 0.05, **P < 0.01, ***P < 0.001. Abbreviations:BCO, breast cancer organoid; CHT, caudal hematopoietic tissue;CI, combination index;DMSO, dimethyl sulfoxide;GFP, green fluorescent protein;Hpf, hours post‐fertilization;Hpi, hours post‐injection;MTT, 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide;PVS, perivitelline space;SD, standard deviation;SEM, standard error of mean;STM, STM2457.
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References

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