Proteasome Inhibitors with a Focus on Bortezomib

Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 17)

Abstract

Proteasome inhibitors have changed the treatment landscape for multiple myeloma and are being increasingly used in the treatment of lymphoma; however, patients eventually have progressive disease and development resistance to treatment. Multiple unique mechanisms of resistance have been identified, and they are unified by reducing a cell’s sensitivity to endoplasmic reticulum stress either from changes intrinsic to the cancer cell or extrinsic to the cancer cell and due to changes in the microenvironment. These pathways primarily involve upregulation of proteasome subunits increasing the capacity to degrade unfolded proteins and plasmacytic differentiation to a more immature plasma cell phenotype with reduced immunoglobulin production. Understanding these mechanisms of resistance can inform therapeutic options to reverse drug resistance or use of novel combinations to synergistically target the unfolded protein response pathway.

Keywords

Ubiquitin proteasome system Proteasome inhibitors Unfolded protein response Plasmacytic differentiation 

Abbreviations

ABC

Activated B-cell

ABCB1

ATP-binding cassette B1

ATF4

Activating transcription factor 4

ATF6

Activating transcription factor 6

BH

BCL-2 homology

BMMSC

Bone marrow mesenchymal stem cell

CYP26

Cytochrome P450 26

DLBCL

Diffuse large B-cell lymphoma

DRD2

Dopamine receptor D-2

E1

Ubiquitin activating enzyme

E2

Ubiquitin conjugating enzyme

E3

Terminal ubiquitin ligase

EGFR

Epidermal growth factor receptor

EIF2α

Eukaryotic Translation Initiation Factor 2α

ER

Endoplasmic reticulum

GCB

Germinal center B-cell

GCN2

EIF2α kinase 4

GLI

Glioma family transcription factors

GRP78

78-kDa glucose regulated protein

HDAC6

Histone deacetylase 6

Hh

Hedgehog pathway

HIV-1

Human immunodeficiency virus-1

HSP

Heat shock protein

Ig

Immunoglobulin

IKK

IκB kinase

IL-6

Interleukin-6

IRE1

Inositol requiring enzyme 1

IRF4

Interferon regulatory factor 4

ISR

Integrated stress response

JAK

Janus associated kinase

MCL

Mantle cell lymphoma

miR

microRNA

MM

Multiple myeloma

NFκB

Nuclear factor kappa B

NHL

Non-Hodgkin’s lymphoma

PADI

Peptidyl arginine deaminase

PERK

EIF2α kinase 3

PI

Proteasome inhibitor

PSMB5

β5 subunit of the proteasome

PTCH1

Patched-1

SHH

Sonic hedgehog

SMO

Smoothened

STAT3

Signal transducer, and activator of transcription 3

TCL

T-cell lymphoma

TGF-β

Transforming growth factor β

TJP1

Tight junction protein 1

TNFα

tumor necrosis factor α

UPR

Unfolded protein response

XBP-1

X-box binding protein 1

Notes

Conflicts of Interest

No potential conflicts of interest were disclosed.

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Hematology and Medical OncologyIcahn School of Medicine at Mount SinaiNew YorkUSA

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