Isabella Berrueta

Background: Human papillomaviruses (HPVs) are responsible for the “most common sexually transmitted viral infection in women and men worldwide,” with up to 85% of women and 95% of men becoming infected at least once during their lifetimes.¹ Typically, the host’s immune system clears up to 70-90% of HPV infections, but if a chronic infection develops it can advance into cancer.² These viruses have been studied in great detail regarding their contribution to cancer development and involvement in over 90% of cervical cancers.¹ The standard treatment for cervical carcinoma consists of gamma irradiation alongside chemotherapy with CDDP (cisplatin), which has been shown to yield a 5-year survival of 52% at most.³ Unfortunately, patients with recurrent tumors have a decreased survival rate under 1 year due to developing drug resistance to CDDP and resistance to radiotherapy.³ The lack of an effective treatment for advanced cervical carcinomas warrants an investigation into potential therapeutic modulators of CDDP sensitivity. This is most relevant for patients with recurrent cervical carcinoma who have acquired CDDP resistance and therefore require higher doses of CDDP with significant side effects.³ Alternatively, BET family proteins (e.g. Brd4) have been studied for their implications in cancer pathogenesis and viral infections.² Because of this, investigations into modulators of BET protein activity and their participation in the HPV life cycle are necessary.³

Objectives: Explore the antiviral mechanisms of BET protein inhibitors in the treatment of HPV-associated cervical cancer, especially regarding modulating resistance to existing therapies.

Search Methods: A search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “HPV,” “papillomavirus,” “BET proteins,” “Brd4,” and “cervical cancer.”

Results: Results indicated that 3 synthesized BET inhibitors were sufficient to effectively suppress viral E1^E4 mRNA transcripts and reduce cell viability in HPV-infected cervical cell lines.⁴ Further analyses revealed that BET inhibition with Brd4 inhibitor JQ1 induced spontaneous DNA damage through creation of transcription-replication conflicts (TCRs), especially in actively replicating cells.⁵ Moreover, experiments in mice demonstrated that JQ1 enhanced tumor regression when combined with radiation therapy.⁶ JQ1 treatment resulted in the most irradiation-induced pro-apoptotic activity even when compared to a Brd4 knockout.⁶ In addition to combating radioresistance, inhibition of Brd4 was shown to reduce viral E6 expression which sensitized HPV-positive cervical cells to CDDP treatment and reversed the chemoresistance.³ Finally, co-delivery of CDDP and JQ1 at a specific 1:5 molar ratio maximized therapeutic efficacy by prolonging drug retention and bioavailability in plasma.⁷

Conclusions: Studies have shown that Brd4 inhibition by JQ1 predisposes cervical cancer cells to radiotherapy and CDDP, proposing a novel therapeutic adjunct strategy to HPV treatment that addresses clinical limitations. These findings further suggest that JQ1 exhibits the potential to improve response to radiation treatment and CDDP chemotherapy in HPV-associated cervical cancers, which is particularly crucial for cases of acquired resistance due to recurrent or advanced tumors. Ongoing clinical trials show promise for the clinical development of JQ1 in cancer treatment, offering hope for improved therapeutic outcomes.

Works Cited:

1. Jain M, Yadav D, Jarouliya U, et al. Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis. Pathogens. 2023;12(12):1380. Published 2023 Nov 23. doi:10.3390/pathogens12121380.
2. Rani AQ, Bonam SR, Zhou J, Li J, Hu H, Liu X. BRD4 as a potential target for human papillomaviruses associated cancer. J Med Virol. 2023;95(12):e29294. doi:10.1002/jmv.29294.
3. Rataj O, Haedicke-Jarboui J, Stubenrauch F, Iftner T. Brd4 inhibition suppresses HPV16 E6 expression and enhances chemoresponse: A potential new target in cervical cancer therapy. Int J Cancer. 2019;144(9):2330-2338. doi:10.1002/ijc.31986.
4. Morse MA, Balogh KK, Brendle SA, et al. BET Bromodomain Inhibitors show Anti-Papillomavirus Activity In Vitro and Block CRPV Wart Growth In Vivo. Antiviral Res. 2018;154:158-165. doi:10.1016/j.antiviral.2018.03.012.
5. Edwards DS, Maganti R, Tanksley JP, et al. BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation. Cell Rep. 2020;32(12):108166. doi:10.1016/j.celrep.2020.108166.
6. Ni M, Li J, Zhao H, et al. BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair. Oncogene. 2021;40(15):2711-2724. doi:10.1038/s41388-021-01735-3.
7. Wang Y, Shen N, Li S, et al. Synergistic Therapy for Cervical Cancer by Codelivery of Cisplatin and JQ1 Inhibiting Plk1-Mutant Trp53 Axis. Nano Lett. 2021;21(6):2412-2421. doi:10.1021/acs.nanolett.0c04402.