Cooperative effect of oncogenic MET and PIK3CA in an HGF-dominant environment in breast cancer

Shuying Liu, Shunqiang Li, Bailiang Wang, Wenbin Liu, Mihai Gagea, Huiqin Chen, Joohyuk Sohn, Napa Parinyanitikul, Tina Primeau, Kim Anh Do, George F. Vande Woude, John Mendelsohn, Naoto T. Ueno, Gordon B. Mills, Debu Tripathy, Ana M. Gonzalez-Angulo

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    Abstract

    There is compelling evidence that oncogenic MET and PIK3CA signaling pathways contribute to breast cancer. However, the activity of pharmacologic targeting of either pathway is modest. Mechanisms of resistance to these monotherapies have not been clarified. Currently, commonly used mouse models are inadequate for studying the HGF–MET axis because mouse HGF does not bind human MET. We established human HGF–MET paired mouse models. In this study, we evaluated the cooperative effects of MET and PIK3CA in an environment with involvement of human HGF in vivo. Oncogenic MET/PIK3CA synergistically induced aggressive behavior and resistance to each targeted therapy in an HGF-paracrine environment. Combined targeting of MET and PI3K abrogates resistance. Associated cell signaling changes were explored by functional proteomics. Consistently, combined targeting of MET and PI3K inhibited activation of associated oncogenic pathways. We also evaluated the response of tumor cells to HGF stimulation using breast cancer patient-derived xenografts (PDX). HGF stimulation induced significant phosphorylation of MET for all PDX lines detected to varying degrees. However, the levels of phosphorylated MET are not correlated with its expression, suggesting that MET expression level cannot be used as a sole criterion to recruit patients to clinical trials for MET-targeted therapy. Altogether, our data suggest that combined targeting of MET and PI3K could be a potential clinical strategy for breast cancer patients, where phosphorylated MET and PIK3CA mutation status would be biomarkers for selecting patients who are most likely to derive benefit from these cotargeted therapy.

    Original languageEnglish (US)
    Pages (from-to)399-412
    Number of pages14
    JournalMolecular cancer therapeutics
    Volume18
    Issue number2
    DOIs
    StatePublished - Feb 2019

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    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Liu, S., Li, S., Wang, B., Liu, W., Gagea, M., Chen, H., Sohn, J., Parinyanitikul, N., Primeau, T., Do, K. A., Vande Woude, G. F., Mendelsohn, J., Ueno, N. T., Mills, G. B., Tripathy, D., & Gonzalez-Angulo, A. M. (2019). Cooperative effect of oncogenic MET and PIK3CA in an HGF-dominant environment in breast cancer. Molecular cancer therapeutics, 18(2), 399-412. https://doi.org/10.1158/1535-7163.MCT-18-0710