Research ResourceCancer therapy

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

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Sci. Signal.  22 Jan 2019:
Vol. 12, Issue 565, eaau2875
DOI: 10.1126/scisignal.aau2875

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Blocking drug resistance

The identification of “cancer drivers” enables the development of targeted therapeutics, but tumors often exhibit—or inevitably develop—resistance to these drugs. Knowing how tumors do this is essential for better and more durable clinical outcomes in patients. Using a multiomics approach, Schwill et al. studied the activities of kinase networks in HER2-positive breast cancer cells in response to HER2-targeted drugs. From these networks, they identified critical proteins, such as the kinase FAK1, that enabled sustained cell survival. Combining an FAK1 inhibitor with a HER2-blocking agent synergistically induced cell death. These findings may inform the development of more effective combination therapies for patients with HER2-positive breast cancer.

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-δ (PRKCD), and Ephrin (EPH) family receptors. These findings reveal potential targets to prevent adaptive resistance to HER2-targeted therapies.

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