Mechanisms of Action and Resistance of Trastuzumab in Breast Cancer

Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 15)

Abstract

Breast cancer affects approximately 1 in 8 women. It is estimated that over 252,710 women in the United States will be diagnosed with breast cancer in 2017. Breast cancer-related deaths have declined over the last two decades as a result of early detection and improved treatment, particularly targeted therapies, such as trastuzumab that targets human epidermal growth factor receptor 2 (HER2), which is frequently overexpressed in breast cancer. However, resistance to trastuzumab, either de novo or acquired resistance, presents a major clinical challenge. Here, we summarize the mechanisms of action and resistance of trastuzumab in breast cancer and discuss potential strategies to overcome resistance.

Keywords

Receptor tyrosine kinase Drug resistance Therapeutic antibodies Small tyrosine kinase inhibitors Breast cancer 

Abbreviations

ADAM10

A disintegrin and metalloproteinase domain-containing protein 10

ADC

Antibody-drug conjugate

ADCC

Antibody-mediated cellular toxicity

AMPK

Adenosine monophosphate (AMP)-activated protein kinase

CTF

Carboxy terminal fragment

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4

ECD

Extracellular domain

EGFR

Epidermal growth factor receptor

EphA2

Ephrin receptor A2

HER2

Human epidermal growth factor receptor 2

HGF

Hepatocyte growth factor

IGF-1

Insulin growth factor-1

IGF-1R

Insulin-like growth factor receptor 1

IGF-2

Insulin growth factor-2

IHC

Immunohistochemistry

JAK

Janus-activated kinase

MAPK

Mitogen-activated protein kinase

MDM2

Murine double minute 2

MUC4

Glycoprotein mucin-4

NK

Natural killer

NSCLC

Non-small cell lung cancer

PD-1

Programmed death-1

PD-L1

Programmed death ligand-1

PI3K

Phosphatidylinositol 3-kinase

PIP2

Phosphatidylinositol-4,5-bisphosphate

PIP3

Phosphatidyl-inositol-3,4,5-trisphosphate

PLCγ

Phospholipase Cγ

PTEN

Phosphatase and tensin homologue

STAT

Signal transducer and activator of transcription

T-DM1

Ado-trastuzumab emtansine

TKI

Tyrosine kinase inhibitor

TNFα

Tumor necrosis factor α

Notes

Acknowledgments

The work was supported by the following grants: National Institutes of Health (CCSG CA016672); Cancer Prevention & Research Institutes of Texas (RP160710 and RP150245); National Breast Cancer Foundation, Inc.; Breast Cancer Research Foundation; Patel Memorial Breast Cancer Endowment Fund; The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund; Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE; MOST 106-2911-I-002-302); Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW106-TDU-B-212-144003); and Center for Biological Pathways.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular and Cellular OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Graduate Institute of Biomedical Sciences and Center for Molecular MedicineChina Medical UniversityTaichungTaiwan
  3. 3.Department of BiotechnologyAsia UniversityTaichungTaiwan

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