Phosphoproteomic mass spectrometry profiling links Src family kinases to escape from HER2 tyrosine kinase inhibition

B. N. Rexer, A. J.L. Ham, C. Rinehart, S. Hill, N. De Matos Granja-Ingram, A. M. González-Angulo, G. B. Mills, B. Dave, Jenny C. Chang, D. C. Liebler, C. L. Arteaga

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

Despite the initial effectiveness of the tyrosine kinase inhibitor lapatinib against HER2 gene-amplified breast cancers, most patients eventually relapse after treatment, implying that tumors acquire mechanisms of drug resistance. To discover these mechanisms, we generated six lapatinib-resistant HER2-overexpressing human breast cancer cell lines. In cells that grew in the presence of lapatinib, HER2 autophosphorylation was undetectable, whereas active phosphoinositide-3 kinase (PI3K)-Akt and mitogen-activated protein kinase (MAPK) were maintained. To identify networks maintaining these signaling pathways, we profiled the tyrosine phosphoproteome of sensitive and resistant cells using an immunoaffinity-enriched mass spectrometry method. We found increased phosphorylation of Src family kinases (SFKs) and putative Src substrates in several resistant cell lines. Treatment of these resistant cells with Src kinase inhibitors partially blocked PI3K-Akt signaling and restored lapatinib sensitivity. Further, SFK mRNA expression was upregulated in primary HER2 tumors treated with lapatinib. Finally, the combination of lapatinib and the Src inhibitor AZD0530 was more effective than lapatinib alone at inhibiting pAkt and growth of established HER2-positive BT-474 xenografts in athymic mice. These data suggest that increased Src kinase activity is a mechanism of lapatinib resistance and support the combination of HER2 antagonists with Src inhibitors early in the treatment of HER2 breast cancers in order to prevent or overcome resistance to HER2 inhibitors.

Original languageEnglish (US)
Pages (from-to)4163-4174
Number of pages12
JournalOncogene
Volume30
Issue number40
DOIs
StatePublished - Oct 6 2011

Keywords

  • HER2
  • Src kinases
  • breast cancer
  • lapatinib
  • tyrosine phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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