TY - JOUR
T1 - Cooperative effect of oncogenic MET and PIK3CA in an HGF-dominant environment in breast cancer
AU - Liu, Shuying
AU - Li, Shunqiang
AU - Wang, Bailiang
AU - Liu, Wenbin
AU - Gagea, Mihai
AU - Chen, Huiqin
AU - Sohn, Joohyuk
AU - Parinyanitikul, Napa
AU - Primeau, Tina
AU - Do, Kim Anh
AU - Vande Woude, George F.
AU - Mendelsohn, John
AU - Ueno, Naoto T.
AU - Mills, Gordon B.
AU - Tripathy, Debu
AU - Gonzalez-Angulo, Ana M.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061023665&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-18-0710
DO - 10.1158/1535-7163.MCT-18-0710
M3 - Article
C2 - 30518672
AN - SCOPUS:85061023665
SN - 1535-7163
VL - 18
SP - 399
EP - 412
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 2
ER -