Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel
| Autor: | Triantafyllia G. Ntouroupi, A.M. Nicholls, Neil Mortensen, Walter F. Bodmer, Jennifer L. Wilding, S Q Ashraf |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
medicine.drug_class
Cetuximab Antineoplastic Agents Biology medicine.disease_cause Monoclonal antibody Lapatinib Antibodies Monoclonal Humanized Tyrosine-kinase inhibitor Trastuzumab Cell Line Tumor medicine Humans skin and connective tissue diseases neoplasms Oligonucleotide Array Sequence Analysis Multidisciplinary Polymorphism Genetic Models Genetic Antibodies Monoclonal Biological Sciences Molecular biology digestive system diseases ErbB Receptors Gene Expression Regulation Neoplastic body regions Genes ras Immune System biology.protein Cancer research Quinazolines KRAS Pertuzumab Antibody Colorectal Neoplasms medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 109(51) |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | A significant proportion of colorectal cancer (CRC) patients are resistant to anti-ERBB1 [avian erythroblastic leukemia viral (v-erb-b) oncogene homolog, receptor for EGF] monoclonal antibodies (Mabs). We evaluated both immune and nonimmune effects of cetuximab (anti-ERBB1 Mab), trastuzumab (anti-ERBB2 Mab), pertuzumab (anti-ERBB2 Mab), and lapatinib (dual ERBB1 and ERBB2 tyrosine kinase inhibitor) in a large well-characterized panel of 64 CRC cell lines to find response predictive tumor characteristics. There was a significant correlation between the direct effects of cetuximab and lapatinib. Both agents were associated ( P = 0.0004) with “triple’ wild-type status in KRAS , BRAF , and PIK3CA exon 20 . Most cell lines were resistant to the direct effects of anti-ERBB2 Mabs, suggesting that the effects of lapatinib might mainly be through ERBB1. Microarray mRNA expression profiles of sensitive and resistant cell lines showed that although ERBB1 receptor or ligand levels did not associate with cetuximab sensitivity, high levels of ERBB2 ( P = 0.036) and amphiregulin ( P = 0.026) predicted sensitivity to lapatinib. However, higher ERBB1 expression predicted susceptibility to cetuximab-induced antibody-dependent cellular cytotoxicity and occurred independently of KRAS/BRAF/PIK3CA mutations ( P = 0.69). Lapatinib may be an effective alternative therapy to cetuximab in triple wild-type tumors. Microarray analysis provides suggestive biomarkers for resistance. ERBB1 levels, independent of mutation status, predict immune killing. Therefore, anti-ERBB1 antibodies may be considered in CRC tumors with higher ERBB1 expression and favorable FcγR polymorphisms. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|