PMID- 18297114 OWN - NLM STAT- MEDLINE DCOM- 20080723 LR - 20211130 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 27 IP - 28 DP - 2008 Jun 26 TI - Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. PG - 3944-56 LID - 10.1038/onc.2008.19 [doi] AB - 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. FAU - Wheeler, D L AU - Wheeler DL AD - Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. FAU - Huang, S AU - Huang S FAU - Kruser, T J AU - Kruser TJ FAU - Nechrebecki, M M AU - Nechrebecki MM FAU - Armstrong, E A AU - Armstrong EA FAU - Benavente, S AU - Benavente S FAU - Gondi, V AU - Gondi V FAU - Hsu, K-T AU - Hsu KT FAU - Harari, P M AU - Harari PM LA - eng GR - R01 CA113448/CA/NCI NIH HHS/United States GR - R01 CA113448-05/CA/NCI NIH HHS/United States GR - R01 CA 113448-01/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20080225 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - PQX0D8J21J (Cetuximab) SB - IM MH - Antibodies, Monoclonal/chemistry/*pharmacology MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Agents/*pharmacology MH - Cell Line, Tumor MH - Cetuximab MH - *Drug Resistance, Neoplasm MH - Endocytosis MH - ErbB Receptors/*genetics/*physiology MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Models, Biological MH - Neoplasms/*drug therapy/pathology MH - RNA Interference MH - Receptor, ErbB-2/metabolism MH - Receptor, ErbB-3/metabolism PMC - PMC2903615 MID - NIHMS214467 EDAT- 2008/02/26 09:00 MHDA- 2008/07/24 09:00 PMCR- 2010/07/13 CRDT- 2008/02/26 09:00 PHST- 2008/02/26 09:00 [pubmed] PHST- 2008/07/24 09:00 [medline] PHST- 2008/02/26 09:00 [entrez] PHST- 2010/07/13 00:00 [pmc-release] AID - onc200819 [pii] AID - 10.1038/onc.2008.19 [doi] PST - ppublish SO - Oncogene. 2008 Jun 26;27(28):3944-56. doi: 10.1038/onc.2008.19. Epub 2008 Feb 25.