A phospho-proteomic study of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type colorectal cancer
© 2021. Crown..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:44 |
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| Enthalten in: |
Cellular oncology (Dordrecht) - 44(2021), 5 vom: 14. Okt., Seite 1197-1206 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Georgiou, Alexandros [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.02.2022 Date Revised 10.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s13402-021-00628-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330056204 |
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| 100 | 1 | |a Georgiou, Alexandros |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A phospho-proteomic study of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type colorectal cancer |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 07.02.2022 | ||
| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. Crown. | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSION: Our findings suggest activation of the PI3K pathway as a mechanism of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type CRC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cetuximab | |
| 650 | 4 | |a Colorectal cancer | |
| 650 | 4 | |a Phospho-proteomics | |
| 650 | 4 | |a Proteomics | |
| 650 | 4 | |a Resistance mechanisms | |
| 650 | 4 | |a Signalling adaptations | |
| 650 | 7 | |a Antineoplastic Agents, Immunological |2 NLM | |
| 650 | 7 | |a KRAS protein, human |2 NLM | |
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| 700 | 1 | |a Vlachogiannis, Georgios |e verfasserin |4 aut | |
| 700 | 1 | |a Pickard, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Valeri, Nicola |e verfasserin |4 aut | |
| 700 | 1 | |a Cunningham, David |e verfasserin |4 aut | |
| 700 | 1 | |a Whittaker, Steven R |e verfasserin |4 aut | |
| 700 | 1 | |a Banerji, Udai |e verfasserin |4 aut | |
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