Combinatorial Treatment with PARP and MAPK Inhibitors Overcomes Phenotype Switch-Driven Drug Resistance in Advanced Melanoma.

Autor:	Ferretti LP; Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland., Böhi F; Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland., Leslie Pedrioli DM; Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland., Cheng PF; Department of Dermatology, University of Zurich, University Hospital Zurich, Schlieren, Switzerland., Ferrari E; Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland., Baumgaertner P; Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Alvarado-Diaz A; Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland., Sella F; Department of Dermatology, University of Zurich, University Hospital Zurich, Schlieren, Switzerland., Cereghetti A; Department of Dermatology, University of Zurich, University Hospital Zurich, Schlieren, Switzerland., Turko P; Department of Dermatology, University of Zurich, University Hospital Zurich, Schlieren, Switzerland., Wright RH; Department of Basic Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Barcelona., De Bock K; Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland., Speiser DE; Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Ferrari R; Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy., Levesque MP; Department of Dermatology, University of Zurich, University Hospital Zurich, Schlieren, Switzerland., Hottiger MO; Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2023 Dec 01; Vol. 83 (23), pp. 3974-3988.
DOI:	10.1158/0008-5472.CAN-23-0485
Abstrakt:	Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors (MAPKi). 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 patients with melanoma. Using a drug screen targeting chromatin regulators in patient-derived three-dimensional MAPKi-resistant melanoma cell cultures, we discovered that PARP inhibitors (PARPi) restore sensitivity to MAPKis, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARPis 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 epithelial-mesenchymal transition-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPKi-sensitive state. The combination of PARP and MAPKis 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 patients with melanoma with PARPis in combination with MAPKis to abrogate acquired therapy resistance. Significance: PARP inhibitors can overcome resistance to MAPK inhibitors by activating autophagic cell death and reversing phenotype switching, suggesting that this synergistic combination could help improve the prognosis of patients with melanoma. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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