FIGURE 5 from PARP Inhibitors Effectively Reduce MAPK Inhibitor Resistant Melanoma Cell Growth and Synergize with MAPK Inhibitors through a Synthetic Lethal Interaction In Vitro and In Vivo

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posted on 2023-09-06, 17:07 authored by Lisa Marie Fröhlich, Heike Niessner, Birgit Sauer, Sofie Kämereit, Eftychia Chatziioannou, Simon Riel, Tobias Sinnberg, Birgit Schittek

MAPKi induce HRD phenotype and thereby act synthetic lethal in combination with PARPi. A, Immunofluorescence of A375 S cells that were treated with 5 μmol/L talazoparib (Tala.), 5 μmol/L vemurafenib (Vem.), or a combination of both inhibitors (Combi.) for 24 hours, or remained untreated (Ctr.). Green: pH2AX, blue: DAPI. 40X magnification was used. Number of pH2AX foci per cell was counted and one-way ANOVA was performed to analyze the differences between the groups. B, Comet Assay was performed using A375 S cells that were treated with either 15 μmol/L talazoparib (Tala.), 5 μmol/L vemurafenib (Vem.), a combination of both drugs (Combi.) for 24 hours or remained untreated (Ctr.). Green: DNA. 10X magnification was used. C, RNA expression of MAPKi sensitive (S), vemurafenib resistant (R), or vemurafenib and trametinib double-resistant (RR) A375 cells after the treatment with 5 μmol/L vemurafenib (Vem.), 10 nmol/L trametinib (Trame.), or 5 μmol/L LY3009120 (LY.) for 24 hours. The relative gene expression of the treated cells compared with the control group is shown.

Funding

Deutsche Forschungsgemeinschaft (DFG)

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ARTICLE ABSTRACT

We show that MAPK inhibitor resistant melanoma cells exhibit low ATM expression increasing their sensitivity toward PARP inhibitors and that a combination of MAPK/PARP inhibitors act synthetically lethal in melanoma cells. Our study shows that PARP inhibitor treatment is a valuable therapy option for patients with melanoma, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression, which could serve as a novel biomarker for treatment response.