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. 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). Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment. TET2/DNMT3A was co-mutated in human lung, breast, skin and kidney cancers...Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment.

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)....Cancer cells and animal models examined with TET2 and DNMT3A-mutant genotype are sensitive to T-dCyd treatment.