Psyrri A, Gkotzamanidou M, Papaxoinis G, Krikoni L, Economopoulou P, Kotsantis I, Anastasiou M, Souliotis V L
Section of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece.
Agios Savvas Anticancer Hospital, Athens, Greece.
ESMO Open. 2021 Apr;6(2):100075. doi: 10.1016/j.esmoop.2021.100075. Epub 2021 Mar 10.
We sought to determine whether DNA damage response (DDR)-related aberrations predict therapeutic benefit in cisplatin-treated head and neck squamous cell carcinoma (HNSCC) patients and how DDR pathways are modulated after treatment with olaparib alone or in combination with cisplatin or durvalumab.
Oxidative stress, abasic sites and DDR-related parameters, including endogenous DNA damage, DNA repair mechanisms and apoptosis rates, were evaluated in HNSCC cell lines and peripheral blood mononuclear cells from 46 healthy controls (HC) and 70 HNSCC patients at baseline and following treatment with cisplatin-containing chemoradiation or nivolumab or enrolled in the OPHELIA phase II trial (NCT02882308; olaparib alone, olaparib plus cisplatin, olaparib plus durvalumab).
HNSCC patients at diagnosis exhibited deregulated DDR-related parameters and higher levels of oxidative stress and abasic sites compared with HC (all P < 0.05). Accordingly, nucleotide excision repair (NER; ERCC1, ERCC2/XPD, XPA, XPC) and base excision repair (APEX1, XRCC1) genes were downregulated in patients versus HC whereas double-strand breaks repair (MRE11A, RAD50, RAD51, XRCC2) and mismatch repair (MLH1, MSH2, MSH3) genes were overexpressed. Corresponding results were obtained in cell lines (all P < 0.001). Excellent correlations were observed between individual ex vivo and in vivo/therapeutic results, with cisplatin non-responders showing higher levels of endogenous DNA damage, augmented oxidative stress and abasic sites, increased NER capacities and reduced apoptosis than responders (all P < 0.05). Also, longer progression-free survival correlated with lower NER capacity (P = 0.037) and increased apoptosis (P = 0.029). Interestingly, treatment with olaparib-containing regimens results in the accumulation of cytotoxic DNA damage and exerts an extra antitumor effect by elevating oxidative stress (all P < 0.05). Nivolumab induced no significant changes in the DDR parameters examined.
Aberrations in DDR signals are implicated in the response to HNSCC chemotherapy and can be exploited as novel therapeutic targets, sensitive/effective non-invasive biomarkers as well as for the design of novel clinical trials.
我们试图确定DNA损伤反应（DDR）相关异常是否能预测顺铂治疗的头颈部鳞状细胞癌（HNSCC）患者的治疗获益，以及DDR通路在单独使用奥拉帕利或与顺铂或度伐利尤单抗联合治疗后是如何被调节的。
在基线时以及接受含顺铂的放化疗或纳武利尤单抗治疗后，或者参加OPHELIA II期试验（NCT02882308；单独使用奥拉帕利、奥拉帕利加顺铂、奥拉帕利加度伐利尤单抗）的70例HNSCC患者以及46例健康对照（HC）的外周血单个核细胞中，评估氧化应激、无碱基位点以及DDR相关参数，包括内源性DNA损伤、DNA修复机制和凋亡率。
与HC相比，诊断时的HNSCC患者表现出DDR相关参数失调，氧化应激和无碱基位点水平更高（所有P<0.05）。因此，与HC相比，患者的核苷酸切除修复（NER；ERCC1、ERCC2/XPD、XPA、XPC）和碱基切除修复（APEX1、XRCC1）基因下调，而双链断裂修复（MRE11A、RAD50、RAD51、XRCC2）和错配修复（MLH1、MSH2、MSH3）基因过表达。在细胞系中也获得了相应结果（所有P<0.001）。在个体体外和体内/治疗结果之间观察到了极好的相关性，与有反应者相比，顺铂无反应者表现出更高水平的内源性DNA损伤、增强的氧化应激和无碱基位点、增加的NER能力以及降低的凋亡（所有P<0.05）。此外，更长的无进展生存期与更低的NER能力（P=0.037）和增加的凋亡（P=0.029）相关。有趣的是，含奥拉帕利方案的治疗导致细胞毒性DNA损伤的积累，并通过提高氧化应激发挥额外的抗肿瘤作用（所有P<0.05）。纳武利尤单抗在所检测的DDR参数中未诱导出显著变化。
DDR信号异常与HNSCC化疗反应有关，可作为新的治疗靶点、敏感/有效的非侵入性生物标志物以及用于设计新的临床试验。
