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

作者：Lorenza P. Ferretti, Flurina Böhi, Deena M. Leslie Pedrioli, Phil F. Cheng, E Ferrari, Petra Baumgaertner, Abdiel Alvarado-Diaz, Federica Sella, Alessandra Cereghetti, Patrick Turko, Roni H. G. Wright, Katrien De Bock, Daniel E. Speiser, Roberto Ferrari, Mitchell P. Levesque, Michael O. Hottiger · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/0008-5472.can-23-0485 · 被引用次数：20 · 研究领域：PARP inhibition in cancer therapy、Melanoma and MAPK Pathways、Telomeres, Telomerase, and Senescence

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 re...