Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD⁺ acute myeloid leukemia.

ABSTRACT: Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase-3 (FLT3) are the most frequent genetic alterations in acute myeloid leukemia (AML) and predict a poor prognosis. FLT3 tyrosine kinase inhibitors (TKIs) provide short-term clinical responses, but the long-term prognosis of FLT3/ITD⁺ AML patients remains poor. Notch signaling is important in numerous types of tumors. However, the role of Notch signaling in FLT3/ITD⁺ AML remains to be elucidated. In the current study, we found that Notch signaling was activated upon FLT3-TKI treatment in FLT3/ITD⁺ cell lines and primary cells. As Notch signaling can be blocked by γ-secretase inhibitors (GSIs), we examined the combinatorial antitumor efficacy of FLT3-TKIs and GSIs against FLT3/ITD⁺

SUBMITTER: Li D 

PROVIDER: S-EPMC7067872 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature