Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer
Author(s)
Schwill, Martin; Tamaskovic, Rastislav; Gajadhar, Aaron; Kast, Florian; White, Forest M.; Plückthun, Andreas; ... Show more Show less![Thumbnail](/bitstream/handle/1721.1/125489/nihms-1027254.pdf.jpg?sequence=4&isAllowed=y)
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Drug-induced compensatory signaling and subsequent rewiring of the signaling pathways that support cell proliferation and survival promote the development of acquired drug resistance in tumors. Here, we sought to analyze the adaptive kinase response in cancer cells after distinct treatment with agents targeting human epidermal growth factor receptor 2 (HER2), specifically those that induce either only temporary cell cycle arrest or, alternatively, apoptosis in HER2-overexpressing cancers. We compared trastuzumab, ARRY380, the combination thereof, and a biparatopic, HER2-targeted designed ankyrin repeat protein (DARPin; specifically, 6L1G) and quantified the phosphoproteome by isobaric tagging using tandem mass tag liquid chromatography/tandem mass spectrometry (TMT LC-MS/MS). We found a specific signature of persistently phosphorylated tyrosine peptides after the nonapoptotic treatments, which we used to distinguish between different treatment-induced cancer cell fates. Next, we analyzed the activation of serine/threonine and tyrosine kinases after treatment using a bait peptide chip array and predicted the corresponding active kinases. Through a combined system-wide analysis, we identified a common adaptive kinase response program that involved the activation of focal adhesion kinase 1 (FAK1), protein kinase C- (PRKCD), and Ephrin (EPH) family receptors. These findings reveal potential targets to prevent adaptive resistance to HER2-targeted therapies.
Date issued
2019-01Department
Massachusetts Institute of Technology. Department of Biological Engineering; Koch Institute for Integrative Cancer Research at MITJournal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Schwill, Martin et al. "Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer." Science Signaling 12, 565 (January 2019): eaau2875 © 2019 The Author(s)
Version: Author's final manuscript
ISSN
1945-0877
1937-9145