Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, St. Louis, MO 63130, USA.
CARIS Life Sciences, Irving, TX 75039, USA.
Int J Mol Sci. 2023 Jun 28;24(13):10771. doi: 10.3390/ijms241310771.
Skin cancers, including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), and melanoma, are the most common malignancies in the United States. Loss of DNA repair pathways in the skin plays a significant role in tumorigenesis. In recent years, targeting DNA repair pathways, particularly homologous recombination deficiency (HRD), has emerged as a potential therapeutic approach in cutaneous malignancies. This review provides an overview of DNA damage and repair pathways, with a focus on HRD, and discusses major advances in targeting these pathways in skin cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to exploit HRD in cancer cells. PARP inhibitors disrupt DNA repair mechanisms by inhibiting PARP enzymatic activity, leading to the accumulation of DNA damage and cell death. The concept of synthetic lethality has been demonstrated in HR-deficient cells, such as those with BRCA1/2 mutations, which exhibit increased sensitivity to PARP inhibitors. HRD assessment methods, including genomic scars, RAD51 foci formation, functional assays, and BRCA1/2 mutation analysis, are discussed as tools for identifying patients who may benefit from PARP inhibitor therapy. Furthermore, HRD has been implicated in the response to immunotherapy, and the combination of PARP inhibitors with immunotherapy has shown promising results. The frequency of HRD in melanoma ranges from 18% to 57%, and studies investigating the use of PARP inhibitors as monotherapy in melanoma are limited. Further research is warranted to explore the potential of PARP inhibition in melanoma treatment.
皮肤癌，包括基底细胞癌（BCC）、皮肤鳞状细胞癌（SCC）和黑色素瘤，是美国最常见的恶性肿瘤。皮肤中 DNA 修复途径的丧失在肿瘤发生中起着重要作用。近年来，靶向 DNA 修复途径，特别是同源重组缺陷（HRD），已成为皮肤恶性肿瘤潜在的治疗方法。本文综述了 DNA 损伤和修复途径，重点介绍了 HRD，并讨论了在皮肤癌中靶向这些途径的主要进展。聚（ADP-核糖）聚合酶（PARP）抑制剂已被开发用于利用癌细胞中的 HRD。PARP 抑制剂通过抑制 PARP 酶活性来破坏 DNA 修复机制，导致 DNA 损伤和细胞死亡的积累。在 HR 缺陷细胞中，如 BRCA1/2 突变细胞中，已经证明了合成致死性的概念，这些细胞对 PARP 抑制剂更敏感。讨论了 HRD 评估方法，包括基因组疤痕、RAD51 焦点形成、功能测定和 BRCA1/2 突变分析，作为识别可能受益于 PARP 抑制剂治疗的患者的工具。此外，HRD 与免疫疗法的反应有关，PARP 抑制剂与免疫疗法的联合显示出有前途的结果。黑色素瘤中 HRD 的频率为 18%至 57%，关于 PARP 抑制剂作为单药治疗黑色素瘤的研究有限。需要进一步研究以探讨 PARP 抑制在黑色素瘤治疗中的潜力。
