Metastatic melanoma is still a difficult‐to‐treat cancer type owing to its frequent resistance mechanisms to targeted and immunotherapy. Therefore, we aimed to unravel novel therapeutic strategies for melanoma patients. Preclinical and clinical studies show that melanoma patients may benefit from a treatment with poly (ADP‐ribose) polymerase (PARP) inhibitors (PARPi). In this study, we focus on PARP1 as a potential biomarker to predict the response of melanoma cells to PARPi therapy. We found that melanoma cells with high basal PARP1 expression exhibit significantly increased cell death after PARPi treatment owing to higher PARP1 trapping compared with melanoma cells with low PARP1 expression. In addition, we could demonstrate that PARP1 expression levels are low in nonmalignant skin cells, and metastatic melanomas show considerably higher PARP1 levels compared with primary melanomas. Most strikingly, we found that high PARP1 levels correlate with worse overall survival of late stage metastasized melanoma patients. In conclusion, we show that PARP1 might act as a biomarker to predict the response to PARPi therapy, and that in particular the late stage metastasized melanoma patients are especially sensitive to PARPi therapy owing to elevated PARP1 expression. Our data suggest that the PARPi cytotoxicity primarily will affect the high PARP1 expressing melanoma cells, rather than the low PARP1 expressing nonmalignant skin cells resulting in only low side effects.

中文翻译：

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PARP1 表达可预测 PARP 抑制剂敏感性，并与黑色素瘤的转移潜力和总生存期相关

由于其对靶向和免疫治疗的常见耐药机制，转移性黑色素瘤仍然是一种难以治疗的癌症类型。因此，我们的目标是为黑色素瘤患者揭示新的治疗策略。临床前和临床研究表明，黑色素瘤患者可能受益于聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）的治疗。在本研究中，我们重点关注 PARP1 作为预测黑色素瘤细胞对 PARPi 治疗反应的潜在生物标志物。我们发现，与低 PARP1 表达的黑色素瘤细胞相比，具有高基础 PARP1 表达的黑色素瘤细胞在 PARPi 处理后表现出显着增加的细胞死亡，这是由于更高的 PARP1 捕获。此外，我们还可以证明，非恶性皮肤细胞中的 PARP1 表达水平较低，并且与原发性黑色素瘤相比，转移性黑色素瘤的 PARP1 水平要高得多。最引人注目的是，我们发现高 PARP1 水平与晚期转移黑色素瘤患者的总生存率较差相关。总之，我们表明 PARP1 可能作为预测 PARPi 治疗反应的生物标志物，特别是晚期转移性黑色素瘤患者由于 PARP1 表达升高而对 PARPi 治疗特别敏感。我们的数据表明，PARPi 细胞毒性主要影响高表达 PARP1 的黑色素瘤细胞，而不是影响低表达 PARP1 的非恶性皮肤细胞，仅产生较低的副作用。