Inhibition of the deubiquitinase USP10 induces degradation of SYK

Abstract

Background There is growing evidence that spleen tyrosine kinase (SYK) is critical for acute myeloid leukaemia (AML) transformation and maintenance of the leukemic clone in AML patients. It has also been found to be over-expressed in AML patients, with activating mutations in foetal liver tyrosine kinase 3 (FLT3), particularly those with internal tandem duplications (FLT3-ITD), where it transactivates FLT3-ITD and confers resistance to treatment with FLT3 tyrosine kinase inhibitors (TKIs). Methods We have previously described a pharmacological approach to treating FLT3-ITD-positive AML that relies on proteasome-mediated FLT3 degradation via inhibition of USP10, the deubiquitinating enzyme (DUB) responsible for cleaving ubiquitin from FLT3. Results Here, we show that USP10 is also a major DUB required for stabilisation of SYK. We further demonstrate that degradation of SYK can be induced by USP10-targeting inhibitors. USP10 inhibition leads to death of cells driven by active SYK or oncogenic FLT3 and potentiates the anti-leukemic effects of FLT3 inhibition in these cells. Conclusions We suggest that USP10 inhibition is a novel approach to inhibiting SYK and impeding its role in the pathology of AML, including oncogenic FLT3-positive AML. Also, given the significant transforming role SYK in other tumours, targeting USP10 may have broader applications in cancer.

Targeting DUBs to degrade oncogenic proteins

“…14 Yang et al provide compelling evidence that SYK can be degraded by inhibition of USP10 leading to cell death in AML cells driven by activated SYK or mutant FLT3. 1 The same group had shown previously that USP10 is also the major deubiquitinating enzyme for FLT3. 15 USP10 inhibition thus leads to dual degradation of FLT3 and SYK, which is beneficial; the combined inhibition of FLT3 and SYK by small molecules is more efficacious than inhibition with either an FLT3 or SYK inhibitor alone in AML.…”

“…6,7 Indeed, SYK has been reported to activate FLT3 through a direct interaction, a finding corroborated in the current study. 1,7 In support of these preclinical findings, two orally bioavailable SYK inhibitors, entospletinib and TAK-659, have been investigated in clinical trials in patients with AML alone and in combination with standard chemotherapy. Early responses have been reported, especially in patients with FLT3-mutated AML and high HOXA9/MEIS1 expression, such as MLL (mixed-lineage leukaemia)-rearranged and NPM1c (cytoplasmic nucleophosmin 1) mutant leukaemia.…”

“…In this issue of the British Journal of Cancer, Yang et al focus on protein degradation as an approach to targeted therapy. 1 Specifically, they discover an approach to the degradation of FLT3 and spleen tyrosine kinase (SYK) through the inhibition of USP10 (ubiquitin-specific protease 10), a deubiquitinating enzyme. FLT3 is recurrently mutated in approximately one-third of AML cases through both internal tandem duplications in the juxtamembrane domain and point mutations in the tyrosine kinase domain.…”

“…Yang et al 1 discovered another parsimonious strategy-to degrade both SYK and FLT3 with a single molecule, that of a deubiquitinase (DUB) inhibitor.…”

“…Yang et al 1 focus on a less explored approach to targeted degradation in cancer-the inhibition of DUBs (Fig. 1).…”