Allavena Eleonora, Croce Michela, Dalmasso Bruna, Profumo Cecilia, Rigo Valentina, Andreotti Virginia, Vanni Irene, Pellegrino Benedetta, Musolino Antonino, Campanini Nicoletta, Bruno William, Mastracci Luca, Zoppoli Gabriele, Tanda Enrica Teresa, Spagnolo Francesco, Ghiorzo Paola, Pastorino Lorenza
Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy.
Cancer Genetics, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.
Int J Mol Sci. 2025 Aug 1;26(15):7420. doi: 10.3390/ijms26157420.
The ataxia-telangiectasia-mutated (ATM) protein plays a crucial role in the DNA damage response, particularly in the homologous recombination (HR) pathway. This study aimed to assess the impact of deleterious variants on homologous recombination deficiency (HRD) and response to PARP inhibitors (PARPi) in melanoma patients, using a cell line established from melanoma tissue of a patient carrying the c.5979_5983del germline variant. Despite proven loss of heterozygosity, lack of ATM activation, and HRD, our model did not show sensitivity to PARPi. We assessed the potential contribution of the Schlafen family member 11 (SLFN11) helicase, whose expression is inversely correlated with PARPi sensitivity in other cancers, to the observed resistance. The ATM mutant cell line lacked SLFN11 expression and featured hypermethylation-mediated silencing of the SLFN11 promoter. While sensitive to the ATR inhibitor (ATRi), the addition of ATRi to PARPi was unable to overcome the resistance. Our findings suggest that mutational status and HRD alone do not adequately account for variations in sensitivity to PARPi in our model. A comprehensive approach is essential for optimizing the exploitation of DNA repair defects and ultimately improving clinical outcomes for melanoma patients.
共济失调毛细血管扩张症突变（ATM）蛋白在DNA损伤反应中起着关键作用，尤其是在同源重组（HR）途径中。本研究旨在利用从一名携带c.5979_5983del种系变体的黑色素瘤患者的黑色素瘤组织建立的细胞系，评估有害变体对黑色素瘤患者同源重组缺陷（HRD）和对聚（ADP-核糖）聚合酶抑制剂（PARPi）反应的影响。尽管已证实杂合性缺失、ATM激活缺失和HRD，但我们的模型对PARPi不敏感。我们评估了Schlafen家族成员11（SLFN11）解旋酶的潜在作用，其表达与其他癌症中PARPi敏感性呈负相关，以解释观察到的耐药性。ATM突变细胞系缺乏SLFN11表达，其特征是SLFN11启动子的甲基化介导的沉默。虽然对ATR抑制剂（ATRi）敏感，但在PARPi中添加ATRi无法克服耐药性。我们的研究结果表明，仅突变状态和HRD不足以解释我们模型中对PARPi敏感性的差异。全面的方法对于优化DNA修复缺陷的利用并最终改善黑色素瘤患者的临床结果至关重要。
