Fibroblast–tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways

Ioannis K. Zervantonakis, Matthew D. Poskus, Alexis L. Scott, Laura M. Selfors, Jia Ren Lin, Deborah A. Dillon, Shailja Pathania, Peter K. Sorger, Gordon B. Mills, Joan S. Brugge

    Research output: Contribution to journalArticlepeer-review

    8 Scopus citations

    Abstract

    Despite the implementation of multiple HER2-targeted therapies, patients with advanced HER2+ breast cancer ultimately develop drug resistance. Stromal fibroblasts represent an abundant cell type in the tumor microenvironment and have been linked to poor outcomes and drug resistance. Here, we show that fibroblasts counteract the cytotoxic effects of HER2 kinase-targeted therapy in a subset of HER2+ breast cancer cell lines and allow cancer cells to proliferate in the presence of the HER2 kinase inhibitor lapatinib. Fibroblasts from primary breast tumors, normal breast tissue, and lung tissue have similar protective effects on tumor cells via paracrine factors. This fibroblast-mediated reduction in drug sensitivity involves increased expression of antiapoptotic proteins and sustained activation of the PI3K/AKT/MTOR pathway, despite inhibition of the HER2 and the RAS-ERK pathways in tumor cells. HER2 therapy sensitivity is restored in the fibroblast cocultures by combination treatment with inhibitors of MTOR or the antiapoptotic proteins BCL-XL and MCL-1. Expression of activated AKT in tumor cells recapitulates the effects of fibroblasts resulting in sustained MTOR signaling and poor lapatinib response. Lapatinib sensitivity was not altered by fibroblasts in tumor cells that exhibited sustained MTOR signaling due to a strong gain-of-function PI3KCA mutation. These findings indicate that in addition to tumor cell-intrinsic mechanisms that cause constitutive PI3K/AKT/MTOR pathway activation, secreted factors from fibroblasts can maintain this pathway in the context of HER2 inhibition. Our integrated proteomic–phenotypic approach presents a strategy for the discovery of protective mechanisms in fibroblast-rich tumors and the design of rational combination therapies to restore drug sensitivity.

    Original languageEnglish (US)
    Pages (from-to)16500-16508
    Number of pages9
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume117
    Issue number28
    DOIs
    StatePublished - Jul 14 2020

    Keywords

    • Breast cancer
    • Cell–cell interactions
    • Drug resistance
    • Fibroblasts
    • Tumor microenvironment

    ASJC Scopus subject areas

    • General

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