Cosci Ilaria, Salizzato Valentina, Del Fiore Paolo, Pigozzo Jacopo, Guarneri Valentina, Mocellin Simone, Ferlin Alberto, Mathlouthi Sara, Piccin Luisa, Garofalo Mariangela
Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35122 Padova, Italy.
Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy.
Pharmaceuticals (Basel). 2025 Aug 21;18(8):1235. doi: 10.3390/ph18081235.
: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent. These alterations drive constitutive activation of the MAPK pathway, promoting uncontrolled cell proliferation, survival, and dissemination. The advent of BRAFi and MEKi has significantly improved outcomes in BRAF V600-mutant melanoma. However, therapeutic resistance remains a major clinical barrier. : This review integrates recent findings from preclinical and clinical studies to delineate resistance mechanisms to BRAF-targeted therapy. It categorizes resistance into (intrinsic), , and , and analyzes their molecular underpinnings, including genetic and epigenetic alterations, pathway reactivation, and microenvironmental interactions. : Primary resistance is linked to pre-existing genetic and epigenetic changes that activate alternative signaling pathways, such as PI3K-AKT. Adaptive and acquired resistance includes secondary BRAF mutations, pathway redundancy, phenotype switching, and immune and stromal interactions. High-throughput sequencing has revealed novel mutations, including NRAS, NF1, and PTEN alterations, that contribute to resistance. : Understanding the multifaceted nature of resistance is critical to improving outcomes in advanced melanoma. This review highlights emerging strategies to overcome resistance, including combinatorial therapies, metabolic targeting, and biomarker-driven approaches, aiming to inform future therapeutic development and precision oncology strategies.
黑色素瘤是最致命的人类皮肤癌，经常携带激活型BRAF突变，其中V600E最为常见。这些改变驱动MAPK途径的组成性激活，促进不受控制的细胞增殖、存活和扩散。BRAF抑制剂（BRAFi）和MEK抑制剂（MEKi）的出现显著改善了BRAF V600突变型黑色素瘤的治疗效果。然而，治疗耐药性仍然是一个主要的临床障碍。 本综述整合了临床前和临床研究的最新发现，以描述对BRAF靶向治疗的耐药机制。它将耐药性分为原发性（内在性）、适应性和获得性，并分析其分子基础，包括基因和表观遗传改变、途径重新激活以及微环境相互作用。 原发性耐药与预先存在的激活替代信号通路（如PI3K-AKT）的基因和表观遗传变化有关。适应性和获得性耐药包括继发性BRAF突变、途径冗余、表型转换以及免疫和基质相互作用。高通量测序揭示了新的突变，包括NRAS、NF1和PTEN改变，这些都导致了耐药性。 了解耐药性的多方面性质对于改善晚期黑色素瘤的治疗效果至关重要。本综述强调了克服耐药性的新兴策略，包括联合治疗、代谢靶向和生物标志物驱动的方法，旨在为未来的治疗发展和精准肿瘤学策略提供信息。
