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Mechanisms Driving Resistance to Proteasome Inhibitors Bortezomib, Carfilzomib, and Ixazomib in Multiple Myeloma

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Resistance to Targeted Therapies in Multiple Myeloma

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 22))

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Abstract

The first clinically available proteasome inhibitor (PI) bortezomib was trialed in multiple myeloma (MM) approximately two decades ago and has since become a mainstay of myeloma therapy, significantly enhancing the overall survival of patients. However, bortezomib resistance continues to be a significant hurdle in the treatment of MM, despite the introduction of next-generation PIs such as carfilzomib and ixazomib. Unlike resistance to some other targeted therapies such as tyrosine kinase inhibitors, bortezomib resistance is highly complex and is able to arise through multiple mechanisms. This chapter discusses the current known mechanisms underlying bortezomib resistance, as well as resistance to the next-generation proteasome inhibitors carfilzomib and ixazomib.

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Abbreviations

ABC:

ATP-binding cassette

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

BiP:

Binding immunoglobulin protein

BMSC:

Bone marrow stromal cell

eIF2É‘:

Eukaryotic initiation factor 2 alpha

ER:

Endoplasmic reticulum

ERAD:

ER-associated decay of proteins

FDA:

US Food and Drug Administration

HDAC6:

Histone deacetylase 6

IGF-1:

Insulin-like growth factor 1

IL:

Interleukin

IRE1:

Inositol-requiring enzyme 1

JNK:

c-Jun N-terminal kinase

MHC-1:

Major histocompatibility complex class I

MM:

Multiple myeloma

MSC:

Mesenchymal stem cells

NF-κB:

Nuclear factor kappa-B

p38MAPK:

p38 mitogen-activated protein kinase

PERK:

PKR-like ER kinase

PFS:

Progression-free survival

PI:

Proteasome inhibitor

PI3K:

Phosphotidylinositol 3-kinase

RIDD:

Regulated IRE1-dependent decay

RRMM:

Relapsed/refractory multiple myeloma

TNF-É‘:

Tumor necrosis factor-alpha

UPR:

Unfolded protein response

XBP1:

X-box binding protein 1

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Acknowledgment

This work was supported by an MF and MH Joyner Scholarship, the RAH Research Fund, an Australian Government Research Training Program Scholarship, a National Health and Medical Research Council of Australia (NHMRC) Peter Doherty Biomedical Early Career Fellowship (1071945), a Royal Australasian College of Physicians Research Establishment Fellowship, the Fay Fuller Foundation, and a Senior Research Fellowship from the NHMRC. The authors would also like to thank Dr. Melissa Pitman for her assistance with the protein structure analysis.

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Author notes

  1. Stuart M. Pitson and Craig T. Wallington-Beddoe contributed equally to this work.

Authors and Affiliations

  1. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide SA, Australia

    Melissa K. Bennett, Stuart M. Pitson & Craig T. Wallington-Beddoe

  2. Adelaide Medical School, University of Adelaide, Adelaide SA, Australia

    Stuart M. Pitson & Craig T. Wallington-Beddoe

  3. School of Biological Sciences, University of Adelaide, Adelaide SA, Australia

    Stuart M. Pitson

  4. Flinders Medical Centre, Bedford Park SA, Australia

    Craig T. Wallington-Beddoe

  5. College of Medicine and Public Health, Flinders University, Bedford Park SA, Australia

    Craig T. Wallington-Beddoe

Authors
  1. Melissa K. Bennett
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  2. Stuart M. Pitson
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  3. Craig T. Wallington-Beddoe
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Corresponding authors

Correspondence to Stuart M. Pitson or Craig T. Wallington-Beddoe .

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Editors and Affiliations

  1. Department of Haematology, Liverpool Hospital, NSW Pathology, NSW, Australia UNSW, Sydney Australia Western Sydney University, Australia Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia

    Silvia CW Ling

  2. Department of Haematology, Liverpool Hospital, UNSW, Sydney, Australia

    Steven Trieu

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Bennett, M.K., Pitson, S.M., Wallington-Beddoe, C.T. (2021). Mechanisms Driving Resistance to Proteasome Inhibitors Bortezomib, Carfilzomib, and Ixazomib in Multiple Myeloma. In: Ling, S.C., Trieu, S. (eds) Resistance to Targeted Therapies in Multiple Myeloma. Resistance to Targeted Anti-Cancer Therapeutics, vol 22. Springer, Cham. https://doi.org/10.1007/978-3-030-73440-4_4

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