Abstract
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) show high efficacy in about 50% of colorectal cancer (CRC) patients with wild-type KRAS. However, < 20% of patients with KRAS wild-type CRC have continued therapeutic effects with these agents, and acquired resistance to treatment has become a serious clinical problem. In this study, to clarify the factors related to acquisition of resistance to cetuximab (Cmab) and establish countermeasures against such acquired resistance, we conducted a comprehensive protein analysis via a proteomics approach using acquired resistance cell lines derived from Cmab-sensitive CRC cell lines and original cell lines. Cmab-acquired resistance cell lines were generated by continuous exposure of SW48 and C99 cell lines to Cmab. Expression of dCK and zinc finger and BTB domain-containing protein 41 (ZBTB41) increased more than 10-fold, and dual specificity protein phosphatase 3 (DUS3) expression decreased by less than 1/10 with acquisition of resistance to Cmab in both C99 and SW48 cell lines. Because overexpression of dCK is known as a positive indicator of efficacy of nucleoside analogs such as cytarabine or gemcitabine, it is considered that nucleoside analogs activated by dCK may be useful agents in treatment of cancers with acquired Cmab-resistance. In the future, we need to clarify the usefulness of these drugs for the treatment of Cmab resistant CRC and to assess the possibility of restoration of Cmab sensitivity by regulation of ZBTB41 and DUS3 expression.Keyword : cetuximab, colorectal cancer, acquired resistance, protein, dCK, ZBTB41
Highlights
Cetuximab was launched in the United States and Europe in 2004 as an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (Mab) for treatment of colorectal cancer (CRC) and pharyngeal cancer
As a countermeasure to acquired resistance to anti-cancer drugs, factors affecting development of acquired resistance were investigated in several studies, and several factors including the RAS-RAF-mitogen activated protein kinase (MAPK)/Erk kinase (MEK)-MAPK signaling pathway, which is significantly involved in the proliferation of cancer cells, were reported to affect tolerance to cetuximab[1,2,3]
The proteins obtained from cetuximabresistance cell lines generated by exposing cetuximabsensitive cell lines to cetuximaband that from original cell lines were analyzed, and increase of deoxycytidine kinase (dCK) and zinc finger and BTB domain-containing protein 41 (ZBTB41) and decrease of dual specificity protein phosphatase 3 (DUS3) were found as a common factor related to acquisition of resistance to cetuximabin both C99 and SW48 cell lines
Summary
Cetuximab was launched in the United States and Europe in 2004 as an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (Mab) for treatment of colorectal cancer (CRC) and pharyngeal cancer. A large-scale clinical trial showed that the presence of genetic variations of KRAS is a resistance factor for antiEGFR Mabs including cetuximab and that the response rate to anti-EGFR Mabs in CRC patients with wild-type KRAS was about 50%(1-3). As a countermeasure to acquired resistance to anti-cancer drugs, factors affecting development of acquired resistance were investigated in several studies, and several factors including the RAS-RAF-mitogen activated protein kinase (MAPK)/Erk kinase (MEK)-MAPK signaling pathway, which is significantly involved in the proliferation of cancer cells, were reported to affect tolerance to cetuximab[1,2,3].
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