ULK1 inhibition as a targeted therapeutic strategy for FLT3-ITD-mutated acute myeloid leukemia

Abstract

Background: In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome. Although uncoordinated 51-like kinase 1 (ULK1), which plays a central role in the autophagy pathway, has emerged as a novel therapeutic target for various cancers, its role in FLT3-ITD AML remains elusive. In this study, we evaluated the effects of ULK1 inhibition on leukemia cell death in FLT3-ITD AML. Method: We evaluated ULK1 expression and the levels of apoptosis and autophagy following ULK1 inhibition in FLT3-ITD AML cell lines and investigated the mechanism underlying apoptosis induced by ULK1 inhibition. Statistical analysis was performed using GraphPad Prism 4.0 (GraphPad Software Inc). Results: FLT3-ITD AML cells showed significantly higher ULK1 expression than FLT3-wild-type (WT) AML cells. Two ULK1 inhibitors, MRT 68921 and SBI-0206965, induced apoptosis in FLT3-ITD AML cells, with relatively minimal effects on FLT3-WT AML cells and normal CD34-positive cells. Apoptosis induction by ULK1 inhibition was associated with caspase pathway activation. Interestingly, ULK1 inhibition paradoxically also induced autophagy, showing synergistic interaction with autophagy inhibitors. Hence, autophagy may act as a prosurvival mechanism in FLT3-ITD AML cells. FLT3-ITD protein degradation and inhibition of the ERK, AKT, and STAT5 pathways were also observed in FLT3-ITD AML cells following treatment with ULK1 inhibitors. Conclusion: ULK1 is a viable drug target and ULK1 inhibition may represent a promising therapeutic strategy against FLT3-ITD AML.

ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils

“…In our present study, increased apoptosis of keratinocytes was observed by knockdown of ULK1 and treatment with ULK1 inhibitor but not by directly inhibiting autophagy with chloroquine or 3-MA, suggesting that ULK1 mediated apoptosis in an autophagyindependent manner. Indeed, previous literature indicates ULK1 inhibitors induced cell apoptosis via caspase activation and dysregulation of Bcl2/Bcl-xl (33)(34)(35). In agreement, we also observed a decrease in transcripts of Bcl2 and Bcl-xl in KCs treated with SBI (data not shown).…”

Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway

“…Chen et al reported that in addition to ULK1, MRT-68921 can inhibit NUAK family SNF1-like kinase 1 (NUAK1), an anti-oxidant molecule, and eventually can exert effective cytotoxicity in various solid cancer cell lines 30 . Moreover, Hwang et al recently reported that both SBI-0206965 and MRT-68921 could induce degradation of internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) protein, thereby exerting cytotoxicity in FLT-ITD AML cells 31 . Thus, SBI-0206965- or MRT-68921-mediated inhibition of other kinases may also contribute to their cytotoxicity in leukemia cells.…”

Circ_HIPK3 Knockdown Inhibits Cell Proliferation, Migration and Invasion of Cholangiocarcinoma Partly via Mediating the miR-148a-3p/ULK1 Pathway

“…Previous papers harbored the view that targeted inhibition of ULK1 contributed to the inhibition of tumor growth and metastasis in diverse cancers. [25][26][27] In CCA, it was documented that ULK1, targeted by miR-373, suppressed CCA cell apoptosis and promoted autophagy, thus promoting CCA development. 28 These views expressed that ULK1 was an oncogene in different cancers, suggesting that ULK1 inhibition might play the same effects with circ_HIPK3 knockdown.…”