Cooperative Effect of Oncogenic MET and PIK3CA in an HGF-Dominant Environment in Breast Cancer.

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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 2 Pg. 399-412 (02 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 30518672 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Bridged Bicyclo Compounds, Heterocyclic
• HGF protein, human
• Indazoles
• Pyrimidines
• Sulfonamides
• Hepatocyte Growth Factor
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Class I Phosphatidylinositol 3-Kinases (genetics)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Hepatocyte Growth Factor (genetics, metabolism)
• Humans
• Indazoles (administration & dosage, pharmacology)
• Mutation
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-met (metabolism)
• Pyrimidines (administration & dosage, pharmacology)
• Sulfonamides (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays