A phospho-proteomic study of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type colorectal cancer
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Published:2021-08-30
Issue:5
Volume:44
Page:1197-1206
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ISSN:2211-3428
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Container-title:Cellular Oncology
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language:en
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Short-container-title:Cell Oncol.
Author:
Georgiou AlexandrosORCID, Stewart Adam, Vlachogiannis GeorgiosORCID, Pickard Lisa, Valeri NicolaORCID, Cunningham DavidORCID, Whittaker Steven R.ORCID, Banerji UdaiORCID
Abstract
Abstract
Purpose
We hypothesised that plasticity in signal transduction may be a mechanism of drug resistance and tested this hypothesis in the setting of cetuximab resistance in patients with KRAS/NRAS/BRAFV600 wild-type colorectal cancer (CRC).
Methods
A multiplex antibody-based platform was used to study simultaneous changes in signal transduction of 55 phospho-proteins in 12 KRAS/NRAS/BRAFV600 wild-type CRC cell lines (6 cetuximab sensitive versus 6 cetuximab resistant) following 1 and 4 h in vitro cetuximab exposure. We validated our results in CRC patient samples (n = 4) using ex vivo exposure to cetuximab in KRAS/NRAS/BRAFV600 cells that were immunomagnetically separated from the serous effusions of patients with known cetuximab resistance.
Results
Differences in levels of phospho-proteins in cetuximab sensitive and resistant cell lines included reductions in phospho-RPS6 and phospho-PRAS40 in cetuximab sensitive, but not cetuximab resistant cell lines at 1 and 4 h, respectively. In addition, phospho-AKT levels were found to be elevated in 3/4 patient samples following ex vivo incubation with cetuximab for 1 h. We further explored these findings by studying the effects of combinations of cetuximab and two PI3K pathway inhibitors in 3 cetuximab resistant cell lines. The addition of PI3K pathway inhibitors to cetuximab led to a significantly higher reduction in colony formation capacity compared to cetuximab alone.
Conclusion
Our findings suggest activation of the PI3K pathway as a mechanism of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type CRC.
Funder
Cancer Research UK
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine,General Medicine
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