Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant.

Abstract

Purpose: Therapeutic strategies against hormonal receptor-positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized.Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis.Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivoConclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395-406. ©2017 AACR.

• Authors: Pei-Yin Hsu, Victoria Shang Wu, Noriko Kanaya, Karineh Petrossian, Hang-Kai Hsu, Duc Nguyen, Daniel Schmolze, Masaya Kai, Chun-Yu Liu, Hannah Lu, Peiguo Chu, Courtney A Vito, Laura Kruper, Joanne Mortimer, Shiuan Chen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 2 Pg. 395-406 (01 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29079660 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Benzoxazoles
• Biomarkers, Tumor
• Estrogens
• Protein Kinase Inhibitors
• Pyrimidines
• Fulvestrant
• MTOR protein, human
• Receptor, ErbB-2
• TOR Serine-Threonine Kinases
• sapanisertib
• Trastuzumab

Topics

• Animals
• Benzoxazoles (pharmacology)
• Biomarkers, Tumor
• Breast Neoplasms (drug therapy, metabolism, mortality, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Estrogens (metabolism)
• Female
• Fulvestrant (pharmacology)
• Humans
• Immunohistochemistry
• Mice
• Mice, Knockout
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Transcriptome
• Trastuzumab (pharmacology)
• Treatment Outcome
• Xenograft Model Antitumor Assays