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

Abstract

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 cisplatincontaining 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 ¼ 0.037) and increased apoptosis (P ¼ 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.

Characterization of Molecular Subtypes in Head and Neck Squamous Cell Carcinoma With Distinct Prognosis and Treatment Responsiveness

“…Genes involved in the UPR and UV response are vital for maintaining proteostasis and genome stability ( Mansilla et al, 2013 ; Strozyk and Kulms, 2013 ; Wang et al, 2019 ; Zhang et al, 2020 ). Previous evidence has functionally implicated these homeostatic mechanisms in HNSCC by regulating key tumor biology processes including cancer cell survival and therapy resistance, while their activities have also been associated with HNSCC prognosis ( Pluquet and Galmiche, 2019 ; Psyrri et al, 2021 ). Furthermore, by overlapping the genes in these three pathways across different cohorts, we identified 101 core genes that were able to subgroup the patients with distinct survival outcomes and molecular profiles.…”

PARP1 Upregulation in Recurrent Oral Cancer and Treatment Resistance

“…Other studies revealed polymorphisms of DDR genes as potential risk factors that promote head and neck cancer progression. Altered expression levels of DNA repair genes, including both upregulation and downregulation, have been shown in oral cancer studies (Wang et al, 2007;Jenkins et al, 20132013;Ali et al, 2017;Dylawerska et al, 2017;Psyrri et al, 2021). Thus, detailed functional studies are necessary to further elucidate how these DDR alterations impact the progression and treatment responses of oral cancer.…”

Current and Emerging Molecular Therapies for Head and Neck Squamous Cell Carcinoma

“…DNA damage response pathways are activated following endogenous and exogenous damage of DNA [179]. Poly (ADP-ribose) polymerase 1 (PARP1) is a member of poly (ADP) ribose moiety enzyme superfamily which repairs single-strand and double-strand breaks [180].…”

“…Moreover, increasing evidence from trials in solid tumours suggests that DNA damage repair (DDR) alterations may predict response to immunotherapy [184]. Recently Psyrri et al, showed that changes in DDR signals are implicated in the response to HNSCC chemotherapy and can be exploited as novel therapeutic targets and sensitive/effective non-invasive biomarkers [179]. A Phase I trial of olaparib at 25 mg orally twice daily with concurrent cetuximab and radiation for heavy smoker patients with locally advanced HNC was well tolerated with reduced dermatitis within the radiation field.…”