Breast Cancer Research and Treatment

, Volume 136, Issue 3, pp 683–692

PI3K independent activation of mTORC1 as a target in lapatinib-resistant ERBB2+ breast cancer cells

  • Anna-Maria Jegg
  • Toby M. Ward
  • Elizabeth Iorns
  • Nicholas Hoe
  • JinYao Zhou
  • Xiaofei Liu
  • Sharat Singh
  • Ralf Landgraf
  • Mark D. Pegram
Preclinical Study

DOI: 10.1007/s10549-012-2252-9

Cite this article as:
Jegg, AM., Ward, T.M., Iorns, E. et al. Breast Cancer Res Treat (2012) 136: 683. doi:10.1007/s10549-012-2252-9

Abstract

Therapies targeting the ERBB2 receptor, including the kinase inhibitor lapatinib (Tykerb, GlaxoSmithKline), have improved clinical outcome for women with ERBB2-amplified breast cancer. However, acquired resistance to lapatinib remains a significant clinical problem, and the mechanisms governing resistance remain poorly understood. We sought to define molecular alterations that confer an acquired lapatinib resistance phenotype in ER−/ERBB2+ human breast cancer cells. ERBB2-amplified SKBR3 breast cancer cells were rendered resistant to lapatinib via culture in increasing concentrations of the drug, and molecular changes associated with a resistant phenotype were interrogated using a collaborative enzyme-enhanced immunoassay platform and immunoblotting techniques for detection of phosphorylated signaling cascade proteins. Interestingly, despite apparent inactivation of the PI3K/AKT signaling pathway, resistant cells exhibited constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) and were highly sensitive to mTOR inhibition with rapamycin and the dual PI3K/mTOR inhibitor NVP-BEZ235. These data demonstrate a role for downstream activation of mTORC1 in the absence of molecular alterations leading to PI3K/AKT hyperactivation as a potential mechanism of lapatinib resistance in this model of ERBB2+ breast cancer and support the rationale of combination or sequential therapy using ERBB2 and mTOR-targeting molecules to prevent or target resistance to lapatinib. Moreover, our data suggest that assessment of mTOR substrate phosphorylation (i.e., S6) may serve as a more robust biomarker to predict sensitivity to mTOR inhibitors in the context of lapatinib resistance than PI3K mutations, loss of PTEN and p-AKT levels.

Keywords

Breast cancer Clinical drug resistance ERBB2-targeted therapy Lapatinib mTOR 

Supplementary material

10549_2012_2252_MOESM1_ESM.ppt (1.6 mb)
Supplementary material 1 (PPT 1649 kb)
10549_2012_2252_MOESM2_ESM.docx (74 kb)
Supplementary material 2 (DOCX 75 kb)

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Anna-Maria Jegg
    • 1
  • Toby M. Ward
    • 1
  • Elizabeth Iorns
    • 3
  • Nicholas Hoe
    • 4
  • JinYao Zhou
    • 4
  • Xiaofei Liu
    • 1
  • Sharat Singh
    • 4
  • Ralf Landgraf
    • 2
  • Mark D. Pegram
    • 1
    • 5
  1. 1.Division of Hematology and OncologyUniversity of Miami Sylvester Comprehensive Cancer CenterMiamiUSA
  2. 2.Department of Biochemistry and Molecular BiologyUniversity of Miami Miller School of MedicineMiamiUSA
  3. 3.Science Exchange, Inc.Palo AltoUSA
  4. 4.Prometheus LaboratoriesSan DiegoUSA
  5. 5.Stanford Cancer InstituteStanford University School of MedicineStanfordUSA

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