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西妥昔单抗耐药的 KRAS/NRAS/BRAF 野生型结直肠癌的磷酸蛋白质组学研究。

A phospho-proteomic study of cetuximab resistance in KRAS/NRAS/BRAF wild-type colorectal cancer.

机构信息

Division of Cancer Therapeutics, The Institute of Cancer Research, Sycamore House, Downs Road, London, SM2 5PT, UK.

Department of Medicine, The Royal Marsden NHS Foundation Trust, Sycamore House, Downs Road, London, SM2 5PT, UK.

出版信息

Cell Oncol (Dordr). 2021 Oct;44(5):1197-1206. doi: 10.1007/s13402-021-00628-7. Epub 2021 Aug 30.

DOI:10.1007/s13402-021-00628-7
PMID:34462871
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8516765/
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/BRAF 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/BRAF 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/BRAF 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/BRAF wild-type CRC.

摘要

目的

我们假设信号转导的可塑性可能是耐药的机制，并在 KRAS/NRAS/BRAF 野生型结直肠癌（CRC）患者的西妥昔单抗耐药环境中检验了这一假说。

方法

使用基于多重抗体的平台研究了 12 个 KRAS/NRAS/BRAF 野生型 CRC 细胞系（6 个西妥昔单抗敏感与 6 个西妥昔单抗耐药）在体外暴露于西妥昔单抗 1 和 4 小时后 55 个磷酸化蛋白信号转导的同时变化。我们使用从已知对西妥昔单抗耐药的患者的浆膜性渗出液中免疫磁分离的 KRAS/NRAS/BRAF 细胞对 CRC 患者样本（n=4）进行了体外暴露于西妥昔单抗的验证。

结果

在西妥昔单抗敏感和耐药细胞系中，磷酸化蛋白水平的差异包括在西妥昔单抗敏感但不是西妥昔单抗耐药细胞系中，分别在 1 和 4 小时时磷酸化-RPS6 和磷酸化-PRAS40 的减少。此外，在 4 例患者样本中，在体外孵育 1 小时后用西妥昔单抗孵育后发现磷酸化-AKT 水平升高。我们通过在 3 个西妥昔单抗耐药细胞系中研究西妥昔单抗和两种 PI3K 通路抑制剂联合的效果进一步探讨了这些发现。与单独使用西妥昔单抗相比，PI3K 通路抑制剂与西妥昔单抗联合使用导致集落形成能力显著降低。

结论

我们的研究结果表明，PI3K 通路的激活是 KRAS/NRAS/BRAF 野生型 CRC 中对西妥昔单抗耐药的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/6d0acee17556/13402_2021_628_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/116b0b6d49d0/13402_2021_628_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/0628141d8329/13402_2021_628_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/71725fa0ef90/13402_2021_628_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/6d0acee17556/13402_2021_628_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/116b0b6d49d0/13402_2021_628_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/0628141d8329/13402_2021_628_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/71725fa0ef90/13402_2021_628_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3db5/8516765/6d0acee17556/13402_2021_628_Fig4_HTML.jpg

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2
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Sci Rep. 2019 Oct 25;9(1):15365. doi: 10.1038/s41598-019-51981-5.
3
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J Gastrointest Oncol. 2022 Dec;13(6):3009-3024. doi: 10.21037/jgo-22-1237.
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Mol Cancer Ther. 2019 Aug;18(8):1396-1404. doi: 10.1158/1535-7163.MCT-18-0727. Epub 2019 Jul 1.
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