Abstract 6928: Combination treatment with cisplatin and PG3 for p53-mutated head & neck cancers

Abstract More than 90% of head & neck (H&N) cancers are squamous cell carcinoma (HNSCC) that occur from the mucosal epithelial tissue of the oral cavity, oropharynx, and larynx. About 30∼40% of stage I or II HNC patients are curable and show improved survival rates after surgery or radiotherapy alone. However, over 60% of stage III or IV HNC patients require chemotherapy. Cisplatin is one of standard chemotherapy drugs for stage III and IV patients. In addition, the mutation frequency of the p53 gene in HNSCC is 65-85%. DNA damage following cisplatin treatment can activate apoptosis via p53 in p53 wild-type cancer cells. In p53-mutated/deleted cancer cells, DNA-damage drugs can lead to cell death through other mechanisms, such as integrated stress response (ISR). There multiple cisplatin-resistance mechanisms were reported. Nucleotide excision repair (NER) is known as the primary strategy for repair of cisplatin-induced DNA damage. Elevated ERCC1 and ERCC5 expression enhance NER and are associated with cisplatin resistance in HNSCC patients. It was reported that ATF4 downregulation promoted cisplatin resistance in p53 mutated and deleted gastric cancers. A small molecule PG3 treatment triggers ISR and leads to cell apoptosis through HRI/eIF2α/ATF4/PUMA pathway in p53-mutated and deleted colorectal cancer cell lines. We hypothesize that (1) combination treatment of PG3 with cisplatin can reduce side effects of cisplatin through reducing the dose of cisplatin, which can be achieved by enhanced induction of integrated stress response, (2) PG3 can sensitize cisplatin-resistant and p53-mutated H&N cancer cells to cisplatin through enhanced induction of integrated stress response. The combination treatment shows synergistic effects in p53-mutated FaDu and Cal27 H&N cancer cells. In combination therapy, use of PG3 allows use of a lower cisplatin dose to achieve a therapeutic benefit. The combined treatment enhances ISR induction, and the ISR contributes to cell apoptosis. We identified that cisplatin or the combination treatment activates the HRI/ATF4/NOXA pathway. NOXA mediates Mcl-1 degradation and is responsible for the combination treatment-induced apoptosis. Citation Format: Xiaobing Tian, Wafik S. El-Deiry. Combination treatment with cisplatin and PG3 for p53-mutated head & neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6928.