HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer

Delphine R. Boulbes, Stefan T. Arold, Gaurav B. Chauhan, Korina V. Blachno, Nanfu Deng, Wei-Chao Chang, Quanri Jin, Tzu-Hsuan Huang, Jung-Mao Hsu, Samuel W. Brady, Chandra Bartholomeusz, John E. Ladbury, Steve Stone, Dihua Yu, Mien-Chie Hung, Francisco J. Esteva

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER family mutations in breast cancer. Because mutations within HER1/EGFR are predictive of response to tyrosine kinase inhibitors (TKI) in lung cancer, we investigated whether mutations in HER family kinase domains are predictive of response to targeted therapy in HER2-overexpressing breast cancer. We sequenced the HER family kinase domains from 76 HER2-overexpressing invasive carcinomas and identified 12 missense variants. Patients whose tumors carried any of these mutations did not respond to HER2 directed therapy in the metastatic setting. We developed mutant cell lines and used structural analyses to determine whether changes in protein conformation could explain the lack of response to therapy. We also functionally studied all HER2 mutants and showed that they conferred an aggressive phenotype and altered effects of the TKI lapatinib. Our data demonstrate that mutations in the finely tuned HER kinase domains play a critical function in breast cancer progression and may serve as prognostic and predictive markers.
Original languageEnglish (US)
Pages (from-to)586-600
Number of pages15
JournalMolecular Oncology
Volume9
Issue number3
DOIs
StatePublished - Nov 11 2014

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Cancer Research

Fingerprint

Dive into the research topics of 'HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer'. Together they form a unique fingerprint.

Cite this