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Combinatorial treatment with PARP and MAPK inhibitors overcomes phenotype switch-driven drug resistance in advanced melanoma

ABSTRACT: Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors. A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of melanoma patients. Using a drug screen targeting chromatin regulators in patient-derived 3D MAPK inhibitor-resistant melanoma cell cultures, we discovered that PARP inhibitors restore sensitivity to MAPK inhibitors, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARP inhibitors induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed EMT-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPK inhibitor-sensitive state. The combination of PARP and MAPK inhibitors synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating melanoma patients with PARP inhibitors in combination with MAPK inhibitors to abrogate acquired therapy resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221241 | GEO | 2023/08/24

REPOSITORIES: GEO

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Combinatorial treatment with PARP and MAPK inhibitors to overcome phenotype switch-driven drug resistance in advanced melanoma

Project description:Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted drugs such as MAPK inhibitors (MAPKi). Here, using a drug screen targeting chromatin regulators in patient-derived 3D melanoma cell cultures, we discovered that PARP inhibitors are capable of restoring MAPKi sensitivity. This synergy was found to be independent of DNA damage repair pathways and was effective both in vitro and in vivo in patients-derived xenografts. Strikingly, through integrated transcriptomic, proteomic and epigenomic analysis, we discovered that PARPi induces lysosomal autophagy which was accompanied by enhanced mitochondrial lipid metabolism that, ultimately, increased antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, we also found that PARP inhibitors regulated EMT-like phenotype switching by dampening the mesenchymal phenotype via transcriptomic and epigenetic rearrangements. This, in turn, redirected melanoma cells towards a proliferative and, thus, MAPKi-sensitive state. Our study provides a scientific rational for treating patients with PARPi in combination with MAPKi to annihilate acquired therapy resistance.

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Proteogenomics analysis to identify acquired resistance-specific alterations in melanoma PDXs on MAPKi therapy

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Project description:In melanoma, a switch from a proliferative melanocytic to an invasive mesenchymal phenotype is based on dramatic transcriptional reprogramming which involves complex interactions between a variety of signaling pathways and their downstream transcriptional regulators. TGFb/SMAD, Hippo/YAP/TAZ and Wnt/b-catenin signaling pathways are major inducers of transcriptional reprogramming and converge at several levels. Here, we report that TGFb/SMAD, YAP/TAZ and b-catenin are all required for a proliferative-to-invasive phenotype switch. Loss and gain of function experimentation, global gene expression analysis, and computational nested effects models revealed the hierarchy between these signaling pathways and identified shared target genes. SMAD-mediated transcription at the top of the hierarchy leads to the activation of YAP/TAZ and of b-catenin, with YAP/TAZ governing an essential sub-program of TGFb-induced phenotype switching. Wnt/b-catenin signaling is situated further downstream and exerts a dual role: it promotes the proliferative, differentiated melanoma cell phenotype and it is essential but not sufficient for SMAD or YAP/TAZ-induced phenotype switching. The results identify epistatic interactions among the signaling pathways underlying melanoma phenotype switching and highlight the priorities in targets for melanoma therapy.

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