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Resistance to Bruton’s Tyrosine Kinase Signaling Pathway Targeted Therapies

  • Yaya ChuEmail author
  • Mitchell S. Cairo
  • Auke Beishuizen
Chapter
First Online:
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 21)

Abstract

Activation of B-cell receptor (BCR) signaling is an important mechanism of the development and growth of B-cell lymphomas. Bruton’s tyrosine kinase (BTK) is a key component of BCR signaling and functions as an important regulator of cell proliferation and cell survival in various B-cell lymphomas. BTK inhibitors, especially ibrutinib, have shown promising anti-tumor activity in preclinical and clinical studies. High response rates of ibrutinib were reported in patients with a variety of B-cell non-Hodgkin lymphoma (B-NHL) such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, clinical evidence shows primary and acquired resistance to BTK inhibitors in patients. Understanding the molecular mechanisms underlying BTK inhibitors’ resistance is of paramount importance. In this review, we highlight the potential resistant mechanisms, which include mutational resistance in BTK, mutational resistance in other proteins than in BTK, chromosomal abnormalities, activation of prosurvival pathways, B-cell lymphoma 2 (BCL-2) family members mediated resistance, and tumor microenvironment mediated resistance. We also discuss the strategies that are utilized to overcome BTK inhibitors’ resistance: non-covalent inhibitors of BTK, alternate kinase inhibitors, combination therapies with other oncogenic inhibitors, BCL-2 inhibitors, anti-CD20 antibodies, anti-CD19 chimeric antigen receptor (CAR) T cells, CD19/CD3 bispecific antibody, or with inhibitors targeting other cellular processes.

Keywords

Targeted therapies Bruton’s tyrosine kinase Ibrutinib Drug resistance B-cell lymphoma Activation of B-cell receptor 

Abbreviations

ABC-DLBCL

Activated B-Cell- Diffuse Large B-cell Lymphoma

AKT

Protein Kinase B

AS-PCR

Allele-Specific Polymerase Chain Reaction

BCR

Activation of B Cell Receptor

BCL-2

B-Cell Lymphoma 2

BL

Burkitt Lymphoma

B-NHL

B cell Non-Hodgkin Lymphoma

BLNK

B-cell Linker Protein

BTK

Bruton’s Tyrosine Kinase

CAR

Chimeric Antigen Receptor

CCND1

Cell Cycle Regulator Cycline D1

CLL

Chronic Lymphocytic Leukemia

CARD11

Caspase Recruitment Domain Family, Member 11

CDK4

Cyclin-Dependent Kinase 4

CR

Complete Response

CRM1/XPO1

Chromosome Region Maintenance1/Exportin-1 Protein

CXCR4

C-X-C Chemokine Receptor type 4

DPPYs

Diphenylpyrimidine Derivatives

DLBCL

Diffuse Large B-cell Lymphoma

DLT

Dose-Limited Toxicities

EFS

Event Free Survival

EGFR

Epidermal Growth Factor Receptor

EIF2A

Eukaryotic Translation Initiation Factor 2A

ERK

Extracellular Signal-Regulated Kinase

FDA

Food and Drug Administration

FL

Follicular Lymphoma

FLIPI

Follicular Lymphoma International Prognostic Index

GBC

Germinal Center B cell

HCL

Hairy cell Lymphoma

HDAC

Histone Deacetylase

HL

Hodgkin Lymphoma

IC50

Half Maximal Inhibitory Concentration

IκB

Inhibitor of Kappa B

IKKb

Inhibitor of Kappa Light Polypeptide Gene Enhancer in B-cells

ITAM

Immunoreceptor Tyrosine-Based Activation Motifs

Itk

Interleukin-2-Inducible T-Cell Kinase

LCK

Lymphocyte-Specific Protein Tyrosine Kinase

LNA

Locked Nucleic Acid

MALT1

Mucosa Associated Lymphoid Tissue Lymphoma Translocation Protein 1

MAPK

Mitogen-Activated Protein Kinase

MCL

Mantle Cell Lymphoma

MLL2

Mixed Lineage Leukemia 2

MOMP

Mitochondrial Outer Membrane Permeability

MPFS

Median Progression-Free Survival

MRD

Minimal Residual Disease

mTOR

Mechanistic Target of Rapamycin

MYD88

Myeloid Differentiation Primary Response Gene (88)

MZL

Marginal zone Lymphoma

NHL

Non-Hodgkin’s Lymphoma

NF-κB

Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells

NGS

Next-Generation Sequencing

NIK

NF-Kappa-B-Inducing Kinase

NSG

NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ

OS

Overall Survival

ORR

Overall Response Rate

P

Phosphorylation

PARP-1

Poly [ADP-ribose] Polymerase 1

PFS

Progression-Free Survival

PH

Pleckstrin Homology

PI3K

Phosphoinositide 3-Kinase

PIM1

Serine/threonine Kinase pim-1

PIP3

Phosphatidylinositol (3,4,5)-Trisphosphate

PLCγ2

1-phosphatidylinositol-4,5-Bisphosphate Phosphodiesterase Gamma-2

PMBCL

Primary Mediastinal B-cell Lymphoma

PR

Partial Response

RPS15

40S Ribosomal Protein S15

R/R

Relapsed/Refractory

scFv

Single Chain Fragment of Variable Region

SFK

Src Family Tyrosine Kinases

SH2

Src Homology 2

SH3

Src Homology 3

SNPs

Single Nucleotide Polymorphisms

SLL

Small Lymphocytic Lymphoma

SYK

Spleen Tyrosine Kinase

Tec

Tyrosine Kinase Expressed in Hepatocellular Carcinoma

TLR

Toll-Like Receptor

TME

Tumor Microenvironment

TRAIL

Tumor Necrosis Factor Related Apoptosis Inducing Ligand

TRAIL-R

Tumor Necrosis Factor Related Apoptosis Inducing Ligand Receptors

Txk

Tyrosine-Protein Kinase TXK

WES

Whole-Exome Sequencing

WM

Waldenström’s Macroglobulinemia

XLA

X-Linked Agammaglobulinemia

2p+

Gain of the Short Arm of Chromosome 2

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Notes

Acknowledgements

This work was supported by the grants from Pediatric Cancer Research Foundation (MSC) and New York Medical College Translational Science Institute, Children Health Translational Research Grant (YC). YC reviewed the literatures, developed the design of the paper and wrote the manuscript. MSC and AB critically revised the manuscript and have approved the final version for publication. The authors would like to thank Erin Morris, RN, and Virginia Davenport, RN for their excellent assistance with the preparation of this manuscript.

Disclosure of Conflict of Interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. 1.Department of PediatricsNew York Medical CollegeValhallaUSA
  2. 2.Departments of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and AnatomyNew York Medical CollegeValhallaUSA
  3. 3.Erasmus MC-Sophia Children’s HospitalUniversity Medical Center Rotterdam and Princess Maxima Center for Pediatric OncologyUtrechtNetherlands

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