Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 2008 Jun 26;27(28):3944-56
Date
02/26/2008Pubmed ID
18297114Pubmed Central ID
PMC2903615DOI
10.1038/onc.2008.19Scopus ID
2-s2.0-46249087766 (requires institutional sign-in at Scopus site) 463 CitationsAbstract
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.
Author List
Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, Gondi V, Hsu KT, Harari PMAuthor
Kun-Tai Hsu MD Assistant Professor in the Plastic Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antibodies, MonoclonalAntibodies, Monoclonal, Humanized
Antineoplastic Agents
Cell Line, Tumor
Cetuximab
Drug Resistance, Neoplasm
Endocytosis
ErbB Receptors
Gene Expression Regulation, Neoplastic
Humans
Models, Biological
Neoplasms
RNA Interference
Receptor, ErbB-2
Receptor, ErbB-3
