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Resistance to HER2-Targeted Therapy

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Resistance to Targeted Therapies in Breast Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 16))

Abstract

HER2 is a member of the ErbB/HER family of receptor tyrosine kinases that promotes the proliferation of a subset of human breast cancers. HER2 is over-expressed in 20–25% of breast cancers and high expression is associated with poor clinical outcomes if not treated with an HER2-targeted drug. Although HER2 does not have a known extracellular ligand, HER2 is the preferred heterodimerization partner for the other HER-family receptors and HER2-containing heterodimers have increased affinity for ligands that bind to those heterodimer partners. The downstream effect is strong signal transduction and tumor cell proliferation. Even in the absence of a ligand, HER2 over-expression by itself can drive tumorigenesis and tumor growth. Given its elevated expression and oncogenic activity, its preferred status as a HER-family signaling partner, and the enhanced activity of HER2-containing heterodimers, HER2 is a valuable pharmacological target for the treatment of HER2+ breast cancer. HER2-targeted agents fall into three general categories: therapeutic antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors. The resistance mechanisms associated with each of these classes of drugs will be reviewed here.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

AUC:

Area under the curve

CDK:

Cyclin dependent kinase

CML:

Chronic myelogenous leukemia

CYP:

Cytochrome P450

DFS:

Disease-free survival

EGF:

Epidermal growth factor

ER:

Estrogen receptor

ERK:

Extracellular signal regulated kinase

FAK:

Focal adhesion kinase

FDA:

United States Food and Drug Administration

HER1:

Human ErbB receptor 1 also known as EGF receptor

HER2:

Human ErbB receptor 2

HER3:

Human ErbB receptor 3

HGF:

Hepatocyte growth factor

HR:

Hazard ratio

HRG:

Heregulin

IGF:

Insulin-like growth factor

IGF-1R:

IGF-1 receptor

MEK:

ERK kinase

MET:

Receptor tyrosine kinase encoded by c-MET gene, also known as hepatocyte growth factor receptor

mTOR:

Mammalian target of rapamycin

mTORC:

mTOR complex

MUC4:

mucin-4

OS:

Overall survival

pCR:

Pathological complete response

PFS:

Progression-free survival

PI3K:

Phosphatidylinositol 3-kinase

PIK3CA :

Gene encoding the p110α catalytic subunit of PI3K

PIP2 :

Phosphatidylinositol-4,5-bisphosphate

PIP3 :

Phosphatidylinositol-3,4,5-trisphosphate

PKA:

Protein kinase A

PR:

Progesterone receptor

PTEN:

Phosphatase and tensin homolog

RTK:

Receptor tyrosine kinase

STAT3:

Signal transducer and activator of transcription 3

TDM:

Therapeutic drug monitoring

T-DM1:

Trastuzumab-emtansine antibody drug conjugate

TGF-α:

Transforming growth factor-α

TKI:

Tyrosine kinase inhibitor

VEGF:

Vascular endothelial growth factor

VEGFR:

VEGF receptor

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Acknowledgements

J.A.M. and S.E.K. are supported by a grant from the National Institutes of Health (GM105898).

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Authors and Affiliations

  1. Department of Cancer Biology, City of Hope, Duarte, CA, USA

    Dirk Theile, Gal Lenz & Susan E. Kane

  2. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany

    Dirk Theile

  3. Department of Chemistry and Biochemistry, California State University Los Angeles, Los Angeles, CA, USA

    Jamil A. Momand

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  1. Dirk Theile
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  2. Gal Lenz
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  4. Susan E. Kane
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  1. Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana, USA

    Jenifer R. Prosperi

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Theile, D., Lenz, G., Momand, J.A., Kane, S.E. (2017). Resistance to HER2-Targeted Therapy. In: Prosperi, J. (eds) Resistance to Targeted Therapies in Breast Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 16. Springer, Cham. https://doi.org/10.1007/978-3-319-70142-4_2

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