Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.

Alexander, Peter B

Chen, Rui

Gong, Chang

Yuan, Lifeng

Jasper, Jeff S

Ding, Yi

Markowitz, Geoffrey J

Yang, Pengyuan

Xu, Xin

McDonnell, Donald P

Song, Erwei

Wang, Xiao-Fan

United States

2017-08-25T20:04:55Z

2017-08-25T20:04:55Z

2017-01-13

Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs.

https://www.ncbi.nlm.nih.gov/pubmed/27903634

M116.754960

1083-351X

https://hdl.handle.net/10161/15359

eng

Elsevier BV

J Biol Chem

10.1074/jbc.M116.754960

breast cancer

cellular senescence

drug resistance

human epidermal growth factor receptor 2 (HER2)

insulin-like growth factor (IGF)

receptor tyrosine kinase

targeted therapy

Breast Neoplasms

Cell Line, Tumor

Drug Resistance, Neoplasm

Female

Gene Expression Regulation, Enzymologic

Gene Expression Regulation, Neoplastic

Humans

Quinazolines

Receptor, ErbB-2

Signal Transduction

Trastuzumab

Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.

Journal article

McDonnell, Donald P|0000-0002-7331-4700

https://www.ncbi.nlm.nih.gov/pubmed/27903634

748

759

2

Basic Science Departments

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Medicine

Medicine, Endocrinology, Metabolism, and Nutrition

Pharmacology & Cancer Biology

School of Medicine

Published

292