Targeting the stress-specific function of replication protein A in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is a significant public health problem, with approximately 400,000 new cases and 200,000 deaths per year worldwide. First-line treatments for OSCC typically include surgery and radiation, with chemotherapy added to enhance the efficacy of radiation (chemoradiation), and to prevent cancer recurrence. Radiation and oral cancer chemotherapeutics eliminate cancer cells largely by disrupting DNA replication to induce replication stress and DNA damage, suggesting the therapeutic benefit of conjunctive targeting of the DNA replication machinery. However, replication functions are essential for normal cell proliferation, leading to unavoidable toxicity that limits the true clinical potential. In this project, we explore a novel idea that the stress-specific function of an essential DNA replication factor can be targeted to effectively and selectively confer toxicity in OSCC. The heterotrimeric replication protein A (RPA) complex binds and stabilizes single strand DNA (ssDNA) via multiple oligonucleotide binding (OB) motifs. RPA-ssDNA not only mediates DNA replication, but also orchestrates replication fork stabilization, DNA repair and activation of the replication checkpoint. Interestingly, a unique OB motif at the N-terminus of the RPA70 subunit (RPA70N) mediates RPA’s binding to, not ssDNA, but multiple proteins involved in the replication stress responses. We hypothesize that this RPA motif is targetable to enhance OSCC treatment responses. RPA upregulation in OSCC has been associated with cancer resistance, and replication stress is a well-established cancer hallmark, supporting the potential selectivity of the treatment. We will develop new transgenic mouse models to study the impact of RPA upregulation and RPA70N mutations on OSCC progression and treatment responses. Combining with these mouse models, we will carry out proof-of-principle, pre-clinical evaluation of a novel small molecule inhibitor of the RPA70N OB motif in OSCC treatment. Our multi-PI team are poised to explore the proposed therapeutic idea, with complementary expertise in RPA, transgenic mouse models, and OSCC.