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

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          Abstract

          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.

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          Author and article information

          Journal
          Oncogene
          Oncogene
          Springer Science and Business Media LLC
          1476-5594
          0950-9232
          Jun 26 2008
          : 27
          : 28
          Affiliations
          [1 ] Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
          Article
          NIHMS214467 onc200819
          10.1038/onc.2008.19
          2903615
          18297114
          0733e7b2-aeb8-46dd-9faa-dba54c31cc7e
          History

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