Zachary Gopin

Introduction: Human papillomavirus (HPV) is the most common sexually transmitted infection in the USA and is a causative agent for cervical, anogenital, and oropharyngeal cancers. The past few decades have seen a significant rise in HPV⁺ HNSCC.^1,2,3 In cervical cancer, it is known that DNA Damage Repair (DDR) pathway activation is critical for HPV replication. However, little is known about the role of DDR in HNSCC.^4,5,6,7 Thus, the ATR and ATM kinases of the DDR pathway, which are activated by single and double-stranded DNA breaks, were investigated in HPV⁺ and HPV^– HNSCC biopsy specimens and cell lines.^4,5,6 Results revealed that Chk1, BRCA1, Rad51, FANCD2, and γH2AX, effector proteins of the ATR pathway, were significantly increased in HPV⁺ HNSCC compared to HPV^– HNSCC.⁶ Some of these effector proteins are being investigated as potential therapeutic targets for the treatment of HPV⁺ HNSCC.^8,9,10,11,12  Methods: HPV⁺ and HPV^– HNSCC cell lines and patient-derived xenograft tumors were treated with cisplatin in the absence or presence of an ATR kinase inhibitor (AZD6738).⁸ HPV⁺ and HPV^– cell lines and patient-derived xenograft tumors were also irradiated in the absence or presence of AZD6738.⁹ In another study, human fibroblasts and HPV⁺ and HPV^– HNSCC cells were co-treated with ionizing radiotherapy (RT) and ATR kinase inhibitor (VE-822).¹⁰ The co-treatment of Chk1 and Chk2 inhibitor (AZD7762) with RT was explored in radioresistant HPV⁺ and HPV^– HNSCC cells and patient-derived xenograft tumors.¹¹ Furthermore, the combined effect of Rad51 inhibitor (B02) and Wee1 inhibitor (AZD1775) was investigated in HPV⁺ and HPV^– HNSCC cell lines and mouse models of oral cancer.¹²  Results: The inhibition of ATR kinase with AZD6738 enhanced HPV⁺ and HPV^– HNSCC responsiveness to cisplatin and RT in both in vivo and in vitro models.^8,9 The combination of RT and VE-822 increased HNSCC cell death, inhibited tumor growth, and was determined to be safe for surrounding normal tissue.¹⁰ Inhibiting Chk1 and Chk2 resulted in increased radiosensitization and therefore rescued radioresistant HPV⁺ and HPV^– HNSCC cells.¹¹ The combined treatment of B02 and AZD1775 caused apoptotic cell death by inducing DNA damage, replication stress, and abnormal mitosis.¹²  Conclusions: These studies suggest that HPV⁺ HNSCC tumors may have adapted to be heavily dependent on their DDR genes for survival. It has been shown that the ATR pathway may play an important role in HPV⁺ HNSCC and therapies targeting the effector proteins in the pathway should be further explored in the treatment of HPV⁺ HNSCC.

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9. Dok R, Glorieux M, Bamps M, Nuyts S. Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers. Int J Mol Sci. 2021;22(4):1504. Published 2021 Feb 3. doi:10.3390/ijms22041504
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11. Bamps M, Dok R, Nuyts S. The DNA Damage Response Is Differentially Involved in HPV-Positive and HPV-Negative Radioresistant Head and Neck Squamous Cell Carcinoma. Cancers (Basel). 2021;13(15):3717. Published 2021 Jul 23. doi:10.3390/cancers13153717
12. Lindemann A, Patel AA, Tang L, et al. Combined Inhibition of Rad51 and Wee1 Enhances Cell Killing in HNSCC Through Induction of Apoptosis Associated With Excessive DNA Damage and Replication Stress. Mol Cancer Ther. 2021;20(7):1257-1269. doi:10.1158/1535-7163.MCT-20-0252