Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin

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Narvi , E , Vaparanta , K , Karrila , A , Chakroborty , D , Knuutila , S , Pulliainen , A , Sundvall , M & Elenius , K 2018 , ' Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin ' , Scientific Reports , vol. 8 , 16579 . https://doi.org/10.1038/s41598-018-34938-y

Title: Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin
Author: Narvi, Elli; Vaparanta, Katri; Karrila, Anna; Chakroborty, Deepankar; Knuutila, Sakari; Pulliainen, Arto; Sundvall, Maria; Elenius, Klaus
Other contributor: University of Helsinki, Medicum


Date: 2018-11-08
Language: eng
Number of pages: 13
Belongs to series: Scientific Reports
ISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-018-34938-y
URI: http://hdl.handle.net/10138/277463
Abstract: Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin.
Subject: ANTICANCER DRUGS
INHIBITORS
STAT3
CHEMOTHERAPY
COMBINATION
GEFITINIB
THERAPY
ACTIVATION
RESISTANCE
APOPTOSIS
3111 Biomedicine
3122 Cancers
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