Mechanisms of acquired resistance to cetuximab: Role of HER (ErbB) family members

D. L. Wheeler, S. Huang, T. J. Kruser, M. M. Nechrebecki, E. A. Armstrong, S. Benavente, V. Gondi, K. T. Hsu, P. M. Harari

Research output: Contribution to journalArticlepeer-review

446 Scopus citations


The epidermal growth factor receptor (EGFR) is a central regulator of proliferation and progression in human cancers. Five EGFR inhibitors, two monoclonal antibodies and three TKIs, have recently gained FDA approval in oncology (cetuximab, panitumumab, erlotinib, gefitinib and lapatinib). These strategies of EGFR inhibition demonstrate major tumor regressions in approximately 10-20% of advanced cancer patients. However, many tumors eventually manifest acquired resistance to treatment. In this study we established and characterized a model to study molecular mechanisms of acquired resistance to the EGFR monoclonal antibody cetuximab. Using high-throughput screening we examined the activity of 42 receptor tyrosine kinases in resistant tumor cells following chronic exposure to cetuximab. Cells developing acquired resistance to cetuximab exhibited increased steady-state EGFR expression secondary to alterations in trafficking and degradation. In addition, cetuximab-resistant cells manifested strong activation of HER2, HER3 and cMET. EGFR upregulation promoted increased dimerization with HER2 and HER3 leading to their transactivation. Blockade of EGFR and HER2 led to loss of HER3 and PI(3)K/Akt activity. These data suggest that acquired resistance to cetuximab is accompanied by dysregulation of EGFR internalization/degradation and subsequent EGFR-dependent activation of HER3. Taken together these findings suggest a rationale for the clinical evaluation of combinatorial anti-HER targeting approaches in tumors manifesting acquired resistance to cetuximab.

Original languageEnglish (US)
Pages (from-to)3944-3956
Number of pages13
Issue number28
StatePublished - Jun 26 2008


  • Acquired resistance
  • Cetuximab
  • EGFR

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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