Abstract 3613: Development of TP53 targeted treatment strategy in esophageal squamous cell carcinoma based on clinical information, TP53 mutation status and p53 RNA expression level
Authors: Kamata Toshiki , Kano Masayuki , Takahashi Masahiko , Murakami Kentaro , Sakata Haruhito , Endo Satoshi , Toyozumi Takeshi , Matsumoto Yasunori , Suito Hiroshi , Yokoyama Masaya , Okada Kouichiro , Shiraishi Tadashi , Ryuzaki Takahiro , Kinoshita Kazuya , Hirasawa Souichiro , Matsubara Hisahiro 
Published: September 2020

[Background] Recently, cancer genomic medicine has been promoted, and he demand for prognostic information and development of new treatments are expected. Especially, gene panel tests using NGS has been covered by insurance on June 1, 2019 in Japan. However, driver mutations for which targeted therapies exist are only a few, and there is no clinically introduced targeted therapies for TP53 which frequently show mutations in solid cancers. There are no other frequent somatic gene mutations in esophageal squamous cell carcinoma (ESCC), and the development of TP53 targeted treatment is considered to be a pressing issue. Although some types of TP53 mutation in ESCC were observed in our research and there have been reports that analyze TP53 mutation status in ESCC, there have been no reports that analyze the difference of prognosis or resistance to treatment depending on TP53 mutation status.

[Objective] To clarify the clinical significance of TP53 mutation status in ESCC.

[Methods] (1) Cell viability assay was tested using ESCC cell lines with different TP53 mutations (wild type, missense/nonsense/frameshift mutation). Drugs which have different effects were used, e.g. Fluorouracil, Cisplatin, APR-246 (which reactivates mutant p53), kevetrin (which activates wild p53). (2) RNA was extracted from ESCC cell lines and PCR was performed. Then, p53 expression level was evaluated.

[Result] (1) APR-246 significantly inhibited the proliferation of ESCC cell lines with missense mutation. (2) Compared with ESCC cell lines with wild type, p53 expression level of cell lines with missense mutation were high, on the other hand, that of cell lines with nonsense/frameshift mutation were low.

[Consideration] APR-246 inhibits the proliferation of ESCC cell lines with missense mutation, because amino acid substitution is caused and then mutant p53 accumulates in ESCC cell lines with missense mutation. The function of ESCC is thought to differ depending on TP53 mutation status, and it is suggested that prognosis may be improved by the selection of drugs according to TP53 mutation status. We integrate and analyze clinical information and TP53 DNA, RNA status from ESCC specimens, and report this theme along with the relevant literature.

Citation Format: Toshiki Kamata, Masayuki Kano, Masahiko Takahashi, Kentaro Murakami, Haruhito Sakata, Satoshi Endo, Takeshi Toyozumi, Yasunori Matsumoto, Hiroshi Suito, Masaya Yokoyama, Kouichiro Okada, Tadashi Shiraishi, Takahiro Ryuzaki, Kazuya Kinoshita, Souichiro Hirasawa, Hisahiro Matsubara. Development of TP53 targeted treatment strategy in esophageal squamous cell carcinoma based on clinical information, TP53 mutation status and p53 RNA expression level [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3613.