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Resistance to Targeted Therapies in Lymphomas pp 111–153Cite as

Resistance to Bruton’s Tyrosine Kinase Signaling Pathway Targeted Therapies

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Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((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.

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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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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.

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Pediatrics, New York Medical College, Valhalla, NY, USA

    Yaya Chu

  2. Departments of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA

    Mitchell S. Cairo

  3. Erasmus MC-Sophia Children’s Hospital, University Medical Center Rotterdam and Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands

    Auke Beishuizen

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  1. Yaya Chu
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Correspondence to Yaya Chu .

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Editors and Affiliations

  1. Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham Children’s Hospital of Alabama, Birmingham, AL, USA

    Ana C. Xavier

  2. Departments of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA

    Mitchell S. Cairo

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Chu, Y., Cairo, M.S., Beishuizen, A. (2019). Resistance to Bruton’s Tyrosine Kinase Signaling Pathway Targeted Therapies. In: Xavier, A., Cairo, M. (eds) Resistance to Targeted Therapies in Lymphomas . Resistance to Targeted Anti-Cancer Therapeutics, vol 21. Springer, Cham. https://doi.org/10.1007/978-3-030-24424-8_6

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