TET2 and DNMT3A mutations and exceptional response to 4'-thio-2'-deoxycytidine in human solid tumor models

  • J Hematol Oncol. 2021 May 26;14(1):83. doi: 10.1186/s13045-021-01091-5.
Sherry X Yang  1 ,  Melinda Hollingshead  2 ,  Larry Rubinstein  2 ,  Dat Nguyen  2 ,  Angelo B A Larenjeira  2 ,  Robert J Kinders  3 ,  Michael Difilippantonio  2 ,  James H Doroshow  2
Affiliations
  • 1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
  • 2. Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 3. Leidos Biomedical Research, Inc., Frederick, MD, USA.
PMID: 34039392 DOI: 10.1186/s13045-021-01091-5
Abstract

Background: Challenges remain on the selection of patients who potentially respond to a class of drugs that target Epigenetics for Cancer treatment. This study aims to investigate TET2/DNMT3A mutations and antitumor activity of a novel epigenetic agent in multiple human Cancer cell lines and animal models.

Methods: Seventeen Cancer cell lines and multiple xenograft models bearing representative human solid tumors were subjected to 4'-thio-2'-deoxycytidine (T-dCyd) or control treatment. Gene mutations in cell lines were examined by whole exome and/or Sanger Sequencing. Specific gene expression was measured in cells and xenograft tumor samples by Western blotting and immunohistochemistry. TET2/DNMT3A mutation status in 47,571 human tumor samples was analyzed at cBioPortal for Cancer Genomics.

Results: Cell survival was significantly inhibited by T-dCyd in breast BT549, lung NCI-H23, melanoma SKMEL5 and renal ACHN Cancer lines harboring deleterious TET2 and nonsynonymous DNMT3A mutations compared to 13 lines without such mutation pattern (P = 0.007). The treatment upregulated p21 and induced cell cycle arrest in NCI-H23 cells, and dramatically inhibited their xenograft tumor growth versus wildtype models. T-dCyd administrations led to a significant p21 increase and near eradication of tumor cells in the double-mutant xenografts by histological evaluation. TET2/DNMT3A was co-mutated in human lung, breast, skin and kidney cancers and frequently in angioimmunoblastic and peripheral T cell lymphomas and several types of leukemia.

Conclusions: Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment. The mutations were detectable in human solid tumors and frequently occur in some hematological malignancies.

Keywords
4′-thio-2′-deoxycytidine (T-dCyd); DNMT3A and TET2 mutations; NCI-H23 cells; Whole exome sequencing; Xenograft tumors; p21.
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