DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival

Abstract

Head and neck cancer (HNC) is a term collectively used to describe a heterogeneous group of tumors that arise in the oral cavity, larynx, nasopharynx, oropharynx, and hypopharynx, and represents the sixth most common type of malignancy worldwide. Despite advances in multimodality treatment, the disease has a recurrence rate of around 50%, and the prognosis of metastatic patients remains poor. HNCs are characterized by a high degree of genomic instability, which involves a vicious circle of accumulating DNA damage, defective DNA damage repair (DDR), and replication stress. Nonetheless, the damage that is induced on tumor cells by chemo and radiotherapy relies on defective DDR processes for a successful response to treatment, and may play an important role in the development of novel and more effective therapies. This review summarizes the current knowledge on the genes and proteins that appear to be deregulated in DDR pathways, their implication in HNC pathogenesis, and the rationale behind targeting these genes and pathways for the development of new therapies. We give particular emphasis on the therapeutic targets that have shown promising results at the pre-clinical stage and on those that have so far been associated with a therapeutic advantage in the clinical setting.

Keywords: DNA damage response; genomic instability; head and neck cancer (HNC); head and neck squamous cell carcinoma (HNSCC); homologous recombination (HR); non-homologous end joining (NHEJ).

Figure 1

Schematic representation of the main DNA repair pathways, the proteins involved in each pathway that are deregulated in HNCs, and the inhibitors that are being investigated as targeted therapeutics. The clarification of the complex interactions between DDR genes with altered expression in HNC can reveal potential biomarkers for predicting clinical outcome and for guiding therapy selection. The investigation of the complex interplay between the different DNA repair mechanisms, and how these are affected by the altered expression of key proteins in HNC, can significantly contribute to the development of new inhibitors for targeted therapy. APEX1: Apurinic/Apyrimidinic Endodeoxyribonuclease 1; ATM: Ataxia Telangiectasia Mutated; ATR: Ataxia Telangiectasia and Rad3-related; BER: Base Excision Repair; BRCA1: Breast Cancer gene 1; BRCA2: Breast Cancer gene 2; CDKi: Cyclin-Dependent Kinase inhibitor; CHK1: Checkpoint kinase 1; CHK2: Checkpoint kinase 2; DDR: DNA damage response; DNA-PKi: DNA-dependent Protein Kinase inhibitor; DSBs: double-strand breaks; ERCC1: Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 1; ERCC2: excision repair cross-complementing rodent repair deficiency Gene 2; ERCC3: excision repair cross-complementing rodent repair deficiency Gene 3; FA-genes: Fanconi Anemia genes; FANCD2: Fanconi Anemia Complementation Group D2; HNC: head and neck cancer; HNSCC: Head and Neck Squamous Cell Carcinoma; HR: Homologous Recombination; MLH1: MutL protein homolog 1; MMR: Mismatch Repair; MSH2: MutS homolog 2; MSH3: MutS Homolog 3; NER: Nucleotide Excision Repair; NHEJ: Nonhomologous End Joining; PARP1/2: Poly(ADP-Ribose) Polymerase 1/2; 2PARPi: Poly (ADP-ribose) Polymerase inhibitor; PMS2: Postmeiotic Segregation Increased 2; SSBs: single-strand breaks; XPA: Xeroderma pigmentosum complementation group A; XPB: xeroderma pigmentosum, complementation group B; XPC: Xeroderma pigmentosum, complementation group C; XPD: Xeroderma Pigmentosum, complementation Group D; XRCC1: X-ray Repair Cross Complementing protein 1.

Figure 2

Overview of the DDR process in HNC pathogenesis, therapeutic resistance, and successful treatment. Genomic instability in HNC is believed to result from the interplay between genetic and environmental factors, and is evidenced by an ever-increasing accumulation of DNA damage, impairment of the DDR mechanism, and a highly unstable genetic environment that is driven by mutagenic stress. On the other hand, tumors that are able to effectively repair the DNA lesions (SSBs and DSBs) induced by chemotherapy and radiation are resistant to these types of treatment and exhibit altered DDR profiles. The identification of these altered DDR-related genes and pathways holds the key to overcoming resistance mechanisms and improving therapeutic outcomes in HNC. Anti-EGFR: Epidermal Growth Factor Receptor antibody; Anti-PD-1: Programmed Death-1 antibody; ATRi: ataxia telangiectasia and Rad3-related inhibitor; ATMi: ataxia telangiectasia mutated inhibitor; CDKi: Cyclin-Dependent Kinase inhibitor; DDR: DNA damage response; DNA-PKi: DNA-dependent Protein Kinase inhibitor; DSBs: double-strand breaks; EMT: endothelial mesenchymal transition; HNC: head and neck cancer; PARPi: Poly (ADP-ribose) Polymerase inhibitor; SSBs: single-strand breaks.