Dataset Information

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.

ABSTRACT: The efficacy of targeting the MAPK signaling pathway in patients with melanoma is limited by the rapid development of resistance mechanisms that result in disease relapse. In this article, we focus on targeting the DNA repair pathway as an antimelanoma therapy, especially in MAPK inhibitor resistant melanoma cells using PARP inhibitors. We found that MAPK inhibitor resistant melanoma cells are particularly sensitive to PARP inhibitor treatment due to a lower basal expression of the DNA damage sensor ataxia-telangiectasia mutated (ATM). As a consequence, MAPK inhibitor resistant melanoma cells have decreased homologous recombination repair activity leading to a reduced repair of double-strand breaks caused by the PARP inhibitors. We validated the clinical relevance of our findings by ATM expression analysis in biopsies from patients with melanoma before and after development of resistance to MAPK inhibitors. Furthermore, we show that inhibition of the MAPK pathway induces a homologous recombination repair deficient phenotype in melanoma cells irrespective of their MAPK inhibitor sensitivity status. MAPK inhibition results in a synthetic lethal interaction of a combinatorial treatment with PARP inhibitors, which significantly reduces melanoma cell growth in vitro and in vivo. In conclusion, this 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.

Significance

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.

SUBMITTER: Frohlich LM

PROVIDER: S-EPMC10478790 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PARP Inhibitors Effectively Reduce MAPK Inhibitor Resistant Melanoma Cell Growth and Synergize with MAPK Inhibitors through a Synthetic Lethal Interaction <i>In Vitro</i> and <i>In Vivo</i>.

Fröhlich Lisa Marie LM Niessner Heike H Sauer Birgit B Kämereit Sofie S Chatziioannou Eftychia E Riel Simon S Sinnberg Tobias T Schittek Birgit B

Cancer research communications 20230905 9

The efficacy of targeting the MAPK signaling pathway in patients with melanoma is limited by the rapid development of resistance mechanisms that result in disease relapse. In this article, we focus on targeting the DNA repair pathway as an antimelanoma therapy, especially in MAPK inhibitor resistant melanoma cells using PARP inhibitors. We found that MAPK inhibitor resistant melanoma cells are particularly sensitive to PARP inhibitor treatment due to a lower basal expression of the DNA damage se ...[more]

PMID: 37674529

Similar Datasets

Project description:BackgroundPhosphodiesterase type 4D (PDE4D) breaks down cyclic AMP (cAMP) reducing the signaling of this intracellular second messenger which plays a major role in melanocyte pathophysiology. In advanced melanoma, expression of PDE4D is increased, plays a role in tumor invasion and is negatively associated with survival. In the current work, we investigated the role of PDE4D in the resistance of BRAF-mutated melanoma to mitogen-activated protein kinase (MAPK) pathway-targeted therapy.MethodsEstablished human melanoma cell line sensitive and resistant to BRAF and MEK inhibitors and tumor tissues from melanoma patients were used in this study. Immunoblotting was used to analyze protein expression and quantitative reverse transcription-PCR was used to analyze mRNA expression. DNA methylation analysis was evaluated via bisulfite treatment followed by quantitative PCR. Cell viability was measured by clonogenic assays or spheroid cultures. Cell xenograft experiments in immunodeficient mice were used to validate the results in vivo.ResultsAnalysis of baseline tumors from patients with BRAFV600E-mutated melanoma treated with MAPK inhibitors showed that higher PDE4D expression in situ predicted worse survival in patients. Furthermore, acquired resistance to BRAF and MEK inhibitors was associated with overexpression of PDE4D in situ and ex vivo. The overexpression of the PDE4D5 isoform in melanoma cells resistant to targeted therapies was explained by demethylation or deletion of a CpG island located upstream of the PDE4D5 promoter. We further showed that PDE4D overexpression allowed RAF1 activation, promoting a switch from BRAF to RAF1 isoform in BRAF-mutated melanoma, favoring resistance to BRAF and MEK inhibitors. As a result, pharmacological inhibition of PDE4 activity impeded the proliferation of resistant cells ex vivo and in vivo. The anti-tumorigenic activity of PDE4 inhibitor was achieved via inhibition of the Hippo pathway which plays an important role in resistance to targeted therapies.ConclusionsIn summary, our research showed that PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors and suggests that PDE4 inhibition is a novel therapeutic option for treatment of BRAF-mutated melanoma patients.