crc-23-0101_fig1.png (439.93 kB)

FIGURE 1 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 resistant melanoma cells are highly susceptible to PARPi treatment. A, MUH cell viability assay of vemurafenib sensitive (S) and resistant (R) melanoma cell lines as well as PDX R cells treated with different concentrations of PARPi (olaparib and talazoparib) starting at 100 μmol/L for 72 hours. Comparison of fits of the nonlinear regression was performed to analyze statistical differences between S and R cells. IC₅₀ levels are shown. B, NSG mice were treated with 2 mg/kg/day talazoparib (Tala.) or the same solvent without talazoparib (Ctr.). The xenograft tumor volume in percent compared with treatment start over time is shown. C, The final tumor volume of the individual mice is depicted. Multiple t test was used to compare the control (Ctr.) group to the talazoparib (Tala.) group. D, Representative pictures of the excised tumors are illustrated.

Funding

Deutsche Forschungsgemeinschaft (DFG)

History

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.