The DNA damage response network in the treatment of head and neck squamous cell carcinoma

ESMO Open

article

A. Psyrri¹  M. Gkotzamanidou¹  G. Papaxoinis²  L. Krikoni³  P. Economopoulou¹  I. Kotsantis¹  M. Anastasiou¹  V.L. Souliotis³ 

[1] Section of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital;Agios Savvas Anticancer Hospital;Institute of Chemical Biology, National Hellenic Research Foundation;First Department of Propaedeutic Internal Medicine and Joint Rheumatology Program, National and Kapodistrian University of Athens

关键词: DNA damage response;    endogenous DNA damage;    oxidative stress;    head and neck squamous cell carcinoma;    cisplatin-containing chemoradiation;    olaparib-containing regimens;   

DOI  :  10.1016/j.esmoop.2021.100075

学科分类：社会科学、人文和艺术（综合）

来源: BMJ Publishing Group

【 摘 要 】

Background 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.Patients and methods 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).Results 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.Conclusions 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.

【 授权许可】

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