American Association for Cancer Research, Cancer Research, 16_Supplement(80), p. LB-107-LB-107, 2020
DOI: 10.1158/1538-7445.am2020-lb-107
Full text: Unavailable
Abstract Background: Challenges remain on the selection of patients who potentially respond to a class of drugs that target the epigenetics for cancer treatment. This study aims to investigate TET2/DNMT3A mutations, their role on prognosis, and relation between the mutations and antitumor activity of a novel epigenetic agent in multiple human cancer cell lines and animal models. Methods: TET2/DNMT3A mutation data in human malignancies were obtained from cBioPortal. Eighteen cancer cell lines and multiple mouse models bearing representative human solid tumors were subjected to 4'-thio-2'-deoxycytidine (T-dCyd) or saline treatment. Gene mutations were examined by whole exome and/or Sanger sequencing in these cell lines. Pharmacodynamic modulation of specific gene expression was analyzed in xenograft tumor samples by immunohistochemistry. Results: TET2 and DNMT3A were frequently mutated in angioimmunoblastic/peripheral T-cell lymphomas, several types of leukemias and cutaneous squamous cell carcinoma, and mutated in lung, breast, skin, and kidney cancers. T-dCyd significantly reduced cell survival in lung NCI-H23, breast BT549, melanoma SKMEL5 and renal ACHN cancer cells that harbor deleterious TET2 and nonsynonymous DNMT3A mutations compared to 14 lines without such pattern of alterations (P = 0.006; 2-sided T-test). Anti-tumor effect was validated in vivo; T-dCyd significantly inhibited tumor growth in mice with TET2/DNMT3A mutation-positive tumors. Histological evaluation revealed a near eradication of tumor cells by T-dCyd in NCI-H23 xenografts. T-dCyd administrations led to a remarkable and persistent p21Waf1/Cip1 increase during treatment (P < 0.0001). In contrast, little activity was observed in xenograft models without this pattern of gene mutations. Conclusions: Cancer cells and animal models examined with TET2 and DNMT3A-mutant genotype are sensitive to T-dCyd treatment. Citation Format: Sherry X. Yang, Larry Rubinstein, Dat Nguyen, Angelo B. Larenjeira, Robert Kinders, Michael Difilippantonio, James H. Doroshow. TET2/DNMT3A mutations and exceptional response to novel epigenetic agent in human malignancies [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 LB-107.