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PTPRS通过SRC驱动对MEK/ERK抑制剂的适应性耐药。

PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC.

作者信息

Davis Thomas B, Yang Mingli, Wang Heiman, Lee Changgong, Yeatman Timothy J, Pledger W Jack

机构信息

Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.

Gibbs Cancer Center & Research Institute, Spartanburg, SC 29303, USA.

出版信息

Oncotarget. 2019 Nov 26;10(63):6768-6780. doi: 10.18632/oncotarget.27335.

DOI:10.18632/oncotarget.27335
PMID:31827720
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6887575/
Abstract

PTPRS is the most commonly mutated receptor tyrosine phosphatase in colorectal cancer (CRC). PTPRS has been shown to directly affect ERK and regulate its activation and nuclear localization. Here we identify that PTPRS may play a significant role in developing adaptive resistance to MEK/ERK inhibitors (MEKi/ERKi) through SRC activation. Moreover, we demonstrate a new clinical approach to averting adaptive resistance through the use of the SRC inhibitor, dasatinib. Our data suggest the potential for dasatinib to enhance the efficacy of MEKi and ERKi by preventing adaptive resistance pathways operating through SRC.

摘要

PTPRS是结直肠癌（CRC）中最常发生突变的受体酪氨酸磷酸酶。已表明PTPRS可直接影响ERK并调节其激活和核定位。在此，我们发现PTPRS可能通过SRC激活在对MEK/ERK抑制剂（MEKi/ERKi）产生适应性耐药中发挥重要作用。此外，我们展示了一种通过使用SRC抑制剂达沙替尼来避免适应性耐药的新临床方法。我们的数据表明，达沙替尼有可能通过阻止通过SRC起作用的适应性耐药途径来增强MEKi和ERKi的疗效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/ee79327a217e/oncotarget-10-6768-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/c2669a754aed/oncotarget-10-6768-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/78cace6da0af/oncotarget-10-6768-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/69e16a32a3be/oncotarget-10-6768-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/e08edc68f9c0/oncotarget-10-6768-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/5de8f92da30e/oncotarget-10-6768-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/90d5d8ff510b/oncotarget-10-6768-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/ee79327a217e/oncotarget-10-6768-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/c2669a754aed/oncotarget-10-6768-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/78cace6da0af/oncotarget-10-6768-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/69e16a32a3be/oncotarget-10-6768-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/e08edc68f9c0/oncotarget-10-6768-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/5de8f92da30e/oncotarget-10-6768-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/90d5d8ff510b/oncotarget-10-6768-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6002/6887575/ee79327a217e/oncotarget-10-6768-g007.jpg

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2
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Clin Cancer Res. 2018 Oct 1;24(19):4874-4886. doi: 10.1158/1078-0432.CCR-17-3697. Epub 2018 Jun 29.
3
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Mol Cell Biochem. 2022 Nov;477(11):2507-2528. doi: 10.1007/s11010-022-04459-4. Epub 2022 May 20.
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