Unravelling the mechanisms of acquired immunomodulatory drug resistance in multiple myeloma
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ICR Authors
Authors
Bird, S
Document Type
Thesis or Dissertation
Date
2023-12-01
Date Accepted
Abstract
Immunomodulatory drugs (IMiDs) are a cornerstone of multiple myeloma
treatment and newer cereblon E3 ligase modulating drugs (CELMoDs) are in
clinical trials. However, a major barrier to improving patient outcomes is the
inevitable development of resistance to these agents.
IMiDs/CELMoDs bind to the cereblon (CRBN) component of the cullinA-RING E3
ubiquitin ligase and designate a new set of substrates for degradation via the
proteasome. Generation of resistance is frequently associated with decreased
CRBN expression, and this is associated with genetic alteration in ~1/3rd of
patients. However, alternative drivers of the low CRBN state, and other
mechanisms of resistance, need to be elucidated.
My aim was to better understand the mechanisms driving acquired IMiD/CELMoD
resistance and develop strategies to treat the resistant disease state. To tackle
this complex problem, I generated and characterised myeloma cell line models
with acquired IMiD/CELMoD resistance and performed multiomics analyses. The
key findings of these analyses were then validated and explored further.
Quantitative proteomics analysis identified common changes in lipid synthesis
proteins across the resistant cell lines and glucose labelling experiments
confirmed altered lipid flux. Proteomic analysis of paired patient samples, from
diagnosis and relapse on IMiD, suggested similar changes in lipid pathways. A
genome wide CRISPR screen performed in a cell line with acquired CELMoD
resistance identified potential novel dependencies in the lipid pathway genes
Stearoyl-CoA Desaturase (SCD) and Membrane Bound Transcription Factor
Peptidase Site 1 (MBTPS1). This work has led to novel insights into lipid pathway
changes in the IMiD/CELMoD-resistant state which may represent targetable
vulnerabilities.
Another novel dependency identified in the resistant lines was SET Domain
Containing 2, Histone Lysine Methyltransferase (SETD2). SETD2 inhibition led
to a greater reduction in proliferation in the IMiD/CELMoD-resistant cell lines
compared to their sensitive control lines, and this was associated with a greater
reduction in Neural Cell Adhesion Molecule 1 (NCAM1/CD56), Epithelial
Membrane Protein 2 (EMP2), and Thymosin Beta 15A (TMSB15A) expression,
suggesting these genes may be key mediators of the effect.
This work provides insights into the generation of IMiD/CELMoD resistance and
identifies potential novel targeted treatment strategies for drug resistant myeloma.
Citation
2023
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Myeloma Biol Therap