Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Abstract

Mucosotropic human papillomaviruses (HPVs) cause prevalent anogenital infections, some of which can progress to cancers. It is imperative to identify efficacious drug candidates, as there are few therapeutic options. We have recapitulated a robust productive program of HPV-18 in organotypic raft cultures of primary human keratinocytes. The HPV E7 protein induces S phase reentry, along with DNA damage response (DDR) in differentiated cells to support viral DNA amplification. A number of small molecule inhibitors of DDR regulators are in clinical use or clinical trials to treat cancers. Here, we used our raft culture system to examine effects of inhibitors of ATR/Chk1 and ATM/Chk2 on HPV infection. The inhibitors impaired S-phase reentry and progression as well as HPV DNA amplification. The Chk1 inhibitor MK-8776 was most effective, reducing viral DNA amplification by 90–99% and caused DNA damage and apoptosis, preferentially in HPV infected cells. We found that this sensitivity was imparted by the E7 protein and report that MK-8776 also caused extensive cell death of cervical cancer cell lines. Furthermore, it sensitized the cells to cisplatin, commonly used to treat advanced cervical cancer. Based on these observations, the Chk1 inhibitors could be potential effective agents to be re-purposed to treat the spectrum of HPV infections in single or combination therapy.

Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers

“…In addition, ATR is one of the major regulators of DDR, and numerous studies underline the role of ATR in the viral replication process of early HPV infections [ 31 , 32 , 33 , 34 ]. However, the role of ATR on DDR response in HPV-positive HNSCC remains understudied.…”

Bayesian Model Infers Drug Repurposing Candidates for Treatment of COVID-19

“…Furthermore, utilization of CHEK1 inhibitors has been successfully used to reduce viral replication. For example, the CHEK1 inhibitor MK-8776 reduced viral DNA amplification by 90-99% in HPV infected cells [43]. Similarly, the CHEK1 inhibitor UCN-01 has been reported to decrease hepatitis B virus DNA yield of HL7702 cells by 80 to 90%, without significantly affecting cell survival [40].…”

Epigenetic Regulation of the Human Papillomavirus Life Cycle

“…Studies over the past decade have established a critical role for the DNA damage response (DDR) in productive replication of high-risk HPV types (Figure 2) [15,87]. DDR pathways serve as an important mechanism for cellular survival by ensuring the fidelity of replication and maintenance of genomic stability [88].…”

“…Expression of high-risk E7 as well as the E1 helicase of low-and high-risk HPV types is sufficient to induce DNA damage and activation of the ATM and ATR DDR pathways [91,[95][96][97]. While high-risk HPVs employ ATM and ATR components to ensure high fidelity of viral gene replication and amplification upon differentiation [15,87], it is currently unclear whether low-risk HPV types also require activation of these DDR pathways.…”