Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer.

TitleSystemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer.
Publication TypeJournal Article
Year of Publication2019
AuthorsSchwill M, Tamaskovic R, Gajadhar AS, Kast F, White FM, Pl├╝ckthun A
JournalSci Signal
Volume12
Issue565
Date Published2019 Jan 22
ISSN1937-9145
Abstract

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.

DOI10.1126/scisignal.aau2875
Alternate JournalSci Signal
PubMed ID30670633
Grant ListR01 CA096504 / CA / NCI NIH HHS / United States
U54 CA210180 / CA / NCI NIH HHS / United States