Abstract
There is a need to develop new, more efficient therapies for head and neck cancer (HNSCC) patients. It is currently unclear whether defects in DNA repair genes play a role in HNSCCs' resistance to therapy. PARP1 inhibitors (PARPi) were found to be “synthetic lethal” in cancers deficient in BRCA1/2 with impaired homologous recombination. Since tumors rarely have these particular mutations, there is considerable interest in finding alternative determinants of PARPi sensitivity. Effectiveness of combined irradiation and PARPi olaparib was evaluated in ten HNSCC cell lines, subdivided into HR-proficient and HR-deficient cell lines using a GFP-based reporter assay. Both groups were equally sensitive to PARPi alone. Combined treatment revealed stronger synergistic interactions in the HR-deficient group. Because HR is mainly active in S-Phase, replication processes were analyzed. A stronger impact of treatment on replication processes (p = 0.04) and an increased number of radial chromosomes (p = 0.003) were observed in the HR-deficient group. We could show that radiosensitization by inhibition of PARP1 strongly correlates with HR competence in a replication-dependent manner. Our observations indicate that PARP1 inhibitors are promising candidates for enhancing the therapeutic ratio achieved by radiotherapy via disabling DNA replication processes in HR-deficient HNSCCs.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer, accounting for roughly 4–6% of all new tumors diagnosed
We have previously shown that breast cancer cell lines show differences in the homologous recombination (HR) capacity they share no common mutations in BRCA1 or BRCA2 [23]
This offers the opportunity to apply PARP1 inhibitors (PARPi) for the treatment of sporadic breast tumors to intensify tumor therapy. To evaluate if this observation is true for other tumor entities, enabling the use of specific PARPi for radiosensitization, HR capacity was analyzed in ten HNSCCs
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer, accounting for roughly 4–6% of all new tumors diagnosed. The poly(adenosine diphosphate ribose) polymerase (PARP) family of DNA end-binding nuclear proteins is involved in one such pathway of DNA repair [3] and inhibition of PARP1 (PARPi) has become a promising therapeutic approach for the treatment of certain types of cancers, especially breast and ovarian cancer. It plays a critical role in the base excision repair pathway (BER), and is a key factor in the repair of single-strand breaks. Ionizing irradiation produces base damage and single strand breaks that the replication fork encounters and tumor cells with a defective regulation of HR and/or replication control are selectively inactivated through perturbed replication processes
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