Abstract
First-line treatments for oral cancer typically include surgery, radiation, and in some cases, chemotherapy. Radiation and oral cancer chemotherapeutics confer cytotoxicity largely by inducing DNA damage, underscoring the importance of the cellular DNA damage repair and response pathways in cancer therapy. However, tumor recurrence and acquired resistance, following the initial response to treatment, remains as a major clinical challenge. By analyzing oral tumor cells derived from the primary and recurrent tumors of the same patient, our study revealed upregulated PARP1 expression in the recurrent tumor cells. Cisplatin and 5-fluorouracil treatment further augmented PARP1 expression in the recurrent, but not the primary, tumor cells. Post-treatment upregulation of PARP1 was dependent on the catalytic activities of PARP and CDK7. Consistent with the established function of PARP1 in DNA repair, we showed that overexpression of PARP1 rendered the primary tumor cells highly resistant to DNA damage treatment. Conversely, PARP inhibition partially reversed the treatment resistance in the recurrent tumor cells; combinatorial treatment using a PARP inhibitor and cisplatin/5-fluorouracil significantly sensitized the tumor response in vivo. Taken together, we reported here PARP1 upregulation as a clinically relevant mechanism involved in oral cancer recurrence, and suggested the clinical benefit of PARP inhibitors, currently approved for the treatment of several other types of cancer, in oral cancer.
Highlights
Oral cancer, including cancers of the mouth and the back of the throat, is the sixth most common cancer worldwide
Upon treatment with cisplatin and 5-FU, two chemotherapeutic drugs used for oral cancer, PARP1 expression was further increased in SCC11B, by approximately 50 and 100%, respectively (Figure 1C)
We reported PARP1 upregulation during the recurrence of oral tumor, using patient-derived cell lines
Summary
Oral cancer, including cancers of the mouth and the back of the throat, is the sixth most common cancer worldwide. First-line treatments for oral cancer typically include surgery and radiation, with chemotherapy added to decrease the possibility of metastasis, to eliminate residual tumor cells after surgery, to enhance the efficacy of radiation, and for patients with confirmed distant metastasis (Casiglia and Woo, 2001; Gau et al, 2019; Johnson et al, 2020). Oral cancer caused by HPV generally responds to the existing treatments, with over 80% 5-year survival rate for stage III and IV patients. Only 10–20% HPV- oral cancer patients at stage III and IV survive the 5-year period. The survival rate of oral cancer has not improved significantly over the past decades. It is important, and urgent, to discover new mechanisms of treatment resistance, and to develop new therapeutics and combinations to overcome resistance in oral cancer
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