2. Academic Validation
  3. Inhibition of the deubiquitinase USP10 induces degradation of SYK

Inhibition of the deubiquitinase USP10 induces degradation of SYK

  • Br J Cancer. 2020 Apr;122(8):1175-1184. doi: 10.1038/s41416-020-0731-z.
Jing Yang  # 1 2,  Chengcheng Meng  # 3,  Ellen Weisberg  # 3 4,  Abigail Case 3,  Ilaria Lamberto 1 2,  Robert S Magin 1 2,  Sophia Adamia 3 4,  Jinhua Wang 1 2,  Nathanael Gray 1 2,  Suiyang Liu 3,  Richard Stone 3 4,  Martin Sattler 3 4,  Sara Buhrlage 5 6,  James D Griffin 7 8
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02215, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02215, MA, USA. [email protected].
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 8 Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 32015510 DOI: 10.1038/s41416-020-0731-z
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.

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