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Novel Therapies to Overcome HER2 Therapy Resistance in Breast Cancer

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Current Applications for Overcoming Resistance to Targeted Therapies

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 20))

Abstract

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that is overexpressed in approximately 15–20% of breast cancers. Trastuzumab was the first HER2-targeted therapy to be approved for clinical use against HER2-overexpressing metastatic breast cancer. However, some patients fail to respond, and many eventually develop progressive disease despite receiving treatment, which may be attributed to the development of a resistant phenotype. New therapies have been developed and approved in combination with trastuzumab for newly diagnosed disease. However, this combinatory regimen also fails and leads to treatment resistance. In this chapter, we review currently used HER2-targeted therapies for breast cancer, available therapies for HER2 antibody therapy-resistant breast cancer, and molecular mechanisms that contribute to the development of resistance. The primary focus is on novel approaches to overcome HER2 therapy resistance in the treatment of breast cancer. We discuss approaches to target HER2 with antibodies, tyrosine kinase inhibitors, or antibody-drug conjugates, as well as targeting downstream signaling, immune pathways, cell cycle regulators, and estrogen receptor signaling. Ultimately, this chapter will provide a detailed overview of the mechanisms of resistance in HER2-positive breast cancers and therapeutic strategies for patients who have developed progressive disease while being treated with HER2 antibody therapy.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

CDK:

Cyclin-dependent kinase

CNS:

Central nervous system

CTLA-4:

Cytotoxic T lymphocyte-associated protein-4

EMT:

Epithelial-mesenchymal transition

ER:

Estrogen receptor

FAK:

Focal adhesion kinase

FDA:

Food and Drug Administration

FoxM1:

Forkhead box M1

GDF15:

Growth differentiation factor 15

HER2:

Human epidermal growth factor receptor 2

HGF:

Hepatocyte growth factor

HR:

Hormone receptor

Hsp90:

Heat shock protein 90

IGF-1R:

Insulin-like growth factor-1 receptor

MAPK:

Mitogen-activated protein kinase

mTOR:

Mammalian target of rapamycin

MUC-4:

Mucin 4

NK:

Natural killer

OS:

Overall survival

pCR:

Pathological complete response

PD-L1:

Programmed death-ligand 1

PFS:

Progression-free survival

PI3K:

Phosphatidylinositol-3-kinase

PTEN:

Phosphatase and tensin homolog

RTK:

Receptor tyrosine kinase

T-DM1:

Trastuzumab emtansine

TIL:

Tumor-infiltrating lymphocyte

TKI:

Tyrosine kinase inhibitor

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Authors and Affiliations

  1. Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA

    Rita Nahta

  2. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    Rita Nahta

  3. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Rita Nahta

  4. Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA

    Rita Nahta

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  1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Myron R. Szewczuk

  2. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Bessi Qorri

  3. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Manpreet Sambi

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Nahta, R. (2019). Novel Therapies to Overcome HER2 Therapy Resistance in Breast Cancer. In: Szewczuk, M., Qorri, B., Sambi, M. (eds) Current Applications for Overcoming Resistance to Targeted Therapies. Resistance to Targeted Anti-Cancer Therapeutics, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-030-21477-7_7

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