Inhibition of the autocrine IL-6–JAK2–STAT3–calprotectin axis as targeted therapy for HR−/HER2+ breast cancers

Ruth Rodriguez-Barrueco, Jiyang Yu, Laura P. Saucedo-Cuevas, Mireia Olivan, David Llobet-Navas, Preeti Putcha, Veronica Castro, Eva M. Murga-Penas, Ana Collazo-Lorduy, Mireia Castillo-Martin, Mariano Alvarez, Carlos Cordon-Cardo, Kevin Kalinsky, Matthew Maurer, Andrea Califano, Jose M. Silva

Onderzoeksoutput: Articlepeer review

79 Citaten (Scopus)

Samenvatting

HER2-positive (HER2+) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR−/HER2+ tumors, eliciting tumor dependency in these cells. Mechanistically, HR−/HER2+ cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6–Janus kinase 2 (JAK2)–STAT3–calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR−/HER2+ breast cancers, opening novel targeted therapeutic opportunities.
Originele taal-2English
Pagina's (van-tot)1631-1648
Aantal pagina's18
TijdschriftGenes & Development
Volume29
Nummer van het tijdschrift15
DOI's
StatusPublished - 1 aug 2015

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