Cooperative Effect of Oncogenic <i>MET</i> and <i>PIK3CA</i> in an HGF-Dominant Environment in Breast Cancer

Abstract

There is compelling evidence that oncogenic <i>MET</i> and <i>PIK3CA</i> 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 <i>MET</i> and <i>PIK3CA</i> in an environment with involvement of human HGF <i>in vivo</i> Oncogenic <i>MET</i>/<i>PIK3CA</i> 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 <i>PIK3CA</i> mutation status would be biomarkers for selecting patients who are most likely to derive benefit from these cotargeted therapy.