1. HUWE1 inhibition as a therapeutic strategy to target MYC in MM
Lisa Crawford
14th March 2018

2. The ubiquitin proteasome system as a molecular target in Multiple Myeloma

3. Huwe1 482 kDa HECT domain E3 ligase
Intrinsic catalytic activity to directly transfer ubiquitin to target protein
Involved in the regulation of DNA damage response, core histones, p53 and MYC
Involved in the regulation of B cell differentiation and function implicated in B cell transformation
Small molecule inhibitors of HUWE1 inhibit MYC function in colorectal cancer cells
HUWE1
Qi et al., Int J Mol Sci, 2012;13:

4. HUWE1 Inhibitors (BI8622 and BI8626)
Peter et al., EMBO Mol Med, 2014;6:
BI8622 and BI8626 decrease viability of MM cell lines, including those resistant to dexamethasome and bortezomib

5. No significant effect on normal bone marrow
BI8622/BI8626 inhibit the proliferation of MM cell lines
Control
BI8622
BI8626
No significant effect on normal bone marrow

6. HUWE1 inhibition leads to a reduction of DNA synthesis
Control
BI8622
Control
Control
BI8622
BI8626
HUWE1 inhibition leads to a reduction of DNA synthesis
Control
BI8622
BI8626
HUWE1 inhibitors induce cellular senescence

7. HUWE1 exerts a cell type-dependent effect on MYC
HUWE1 inhibition decreases MYC expression
Peter et al, 2014, EMBO
HUWE1 inhibition leads to decreased expression of MYC-dependent target genes
Myant et al, 2017, EMBO

8. Identification of candidate substrates of HUWE1 Snapshot proteomics TM
NTC
HUWE1 KD
HuProt Protein Arrays
2314 changes in protein ubiquitination

9. Ingenuity Pathway Analysis
Input
UbiQapture
HUWE1 inhibition induces degradation of MYC

10. Combination of HUWE1 inhibitors with conventional MM therapies is synergistic
Carfilzomib
Dexamethasone
Pomalidomide

11. Summary Inhibitors of HUWE1 lead to growth arrest of MM cell lines.
HUWE1 inhibitors act in synergy with conventional MM therapies.
HUWE1 inhibitors decrease expression of MYC and MYC-dependent target genes.
Studies are ongoing to elucidate the molecular mechanism of MYC downregulation following HUWE1 inhibition.

12. Acknowledgements CCRCB Blood Cancer Research Group Collaborators
Dr. Sandra Irvine
Prof. Ken Mills
Cliona Johnston
Jonathan Morgan
Claudia Hamilton
Collaborators
Dr. Dharminder Chauhan
Dana Farber Cancer Institute, Harvard
Dr. Andrew Chantry
Dr. Michelle Lawson
University of Sheffield
Professor Krishnaraj Rajalingam
Mainz University Medical Centre
Professor Martin Eilers
University of Wurzberg