Dual mTOR kinase inhibitor MLN0128 sensitize HR þ /HER2 þ breast cancer patient-Derived xenografts to trastuzumab or fulvestrant

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: Therapeutic strategies against hormonal receptor–positive (HR þ )/HER2 þ breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR þ /HER2 þ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 þ 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 ERa signaling predominantly regulate tumor growth of the two HR þ /HER2 þ 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 þ /HER2 þ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR þ /HER2 þ 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.

Original languageEnglish
Pages (from-to)395-406
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number2
DOIs
Publication statusPublished - Jan 15 2018

Fingerprint

Sirolimus
Heterografts
Phosphotransferases
Breast Neoplasms
Neoplasms
Growth
RNA Sequence Analysis
Therapeutics
Protein Array Analysis
Precision Medicine
Estrogen Receptor Modulators
fulvestrant
Trastuzumab
INK128
Pharmaceutical Preparations
Estrogens
Research Design
Cell Proliferation
Clinical Trials
Population

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Dual mTOR kinase inhibitor MLN0128 sensitize HR þ /HER2 þ breast cancer patient-Derived xenografts to trastuzumab or fulvestrant . / Hsu, Pei Yin; Wu, Victoria Shang; Kanaya, Noriko; Petrossian, Karineh; Hsu, Hang Kai; Nguyen, Duc; Schmolze, Daniel; Kai, Masaya; Liu, Chun Yu; Lu, Hannah; Chu, Peiguo; Vito, Courtney A.; Kruper, Laura; Mortimer, Joanne; Chen, Shiuan.

In: Clinical Cancer Research, Vol. 24, No. 2, 15.01.2018, p. 395-406.

Research output: Contribution to journalArticle

Hsu, PY, Wu, VS, Kanaya, N, Petrossian, K, Hsu, HK, Nguyen, D, Schmolze, D, Kai, M, Liu, CY, Lu, H, Chu, P, Vito, CA, Kruper, L, Mortimer, J & Chen, S 2018, ' Dual mTOR kinase inhibitor MLN0128 sensitize HR þ /HER2 þ breast cancer patient-Derived xenografts to trastuzumab or fulvestrant ', Clinical Cancer Research, vol. 24, no. 2, pp. 395-406. https://doi.org/10.1158/1078-0432.CCR-17-1983
Hsu, Pei Yin ; Wu, Victoria Shang ; Kanaya, Noriko ; Petrossian, Karineh ; Hsu, Hang Kai ; Nguyen, Duc ; Schmolze, Daniel ; Kai, Masaya ; Liu, Chun Yu ; Lu, Hannah ; Chu, Peiguo ; Vito, Courtney A. ; Kruper, Laura ; Mortimer, Joanne ; Chen, Shiuan. / Dual mTOR kinase inhibitor MLN0128 sensitize HR þ /HER2 þ breast cancer patient-Derived xenografts to trastuzumab or fulvestrant In: Clinical Cancer Research. 2018 ; Vol. 24, No. 2. pp. 395-406.
@article{3b0425f735c1497d8ada89034444017a,
title = "Dual mTOR kinase inhibitor MLN0128 sensitize HR {\th} /HER2 {\th} breast cancer patient-Derived xenografts to trastuzumab or fulvestrant",
abstract = "Purpose: Therapeutic strategies against hormonal receptor–positive (HR {\th} )/HER2 {\th} breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR {\th} /HER2 {\th} patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 {\th} 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 ERa signaling predominantly regulate tumor growth of the two HR {\th} /HER2 {\th} 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 {\th} /HER2 {\th} cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR {\th} /HER2 {\th} 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.",
author = "Hsu, {Pei Yin} and Wu, {Victoria Shang} and Noriko Kanaya and Karineh Petrossian and Hsu, {Hang Kai} and Duc Nguyen and Daniel Schmolze and Masaya Kai and Liu, {Chun Yu} and Hannah Lu and Peiguo Chu and Vito, {Courtney A.} and Laura Kruper and Joanne Mortimer and Shiuan Chen",
year = "2018",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-17-1983",
language = "English",
volume = "24",
pages = "395--406",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Dual mTOR kinase inhibitor MLN0128 sensitize HR þ /HER2 þ breast cancer patient-Derived xenografts to trastuzumab or fulvestrant

AU - Hsu, Pei Yin

AU - Wu, Victoria Shang

AU - Kanaya, Noriko

AU - Petrossian, Karineh

AU - Hsu, Hang Kai

AU - Nguyen, Duc

AU - Schmolze, Daniel

AU - Kai, Masaya

AU - Liu, Chun Yu

AU - Lu, Hannah

AU - Chu, Peiguo

AU - Vito, Courtney A.

AU - Kruper, Laura

AU - Mortimer, Joanne

AU - Chen, Shiuan

PY - 2018/1/15

Y1 - 2018/1/15

N2 - Purpose: Therapeutic strategies against hormonal receptor–positive (HR þ )/HER2 þ breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR þ /HER2 þ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 þ 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 ERa signaling predominantly regulate tumor growth of the two HR þ /HER2 þ 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 þ /HER2 þ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR þ /HER2 þ 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.

AB - Purpose: Therapeutic strategies against hormonal receptor–positive (HR þ )/HER2 þ breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR þ /HER2 þ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 þ 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 ERa signaling predominantly regulate tumor growth of the two HR þ /HER2 þ 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 þ /HER2 þ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR þ /HER2 þ 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.

UR - http://www.scopus.com/inward/record.url?scp=85040667398&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040667398&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-17-1983

DO - 10.1158/1078-0432.CCR-17-1983

M3 - Article

C2 - 29079660

AN - SCOPUS:85040667398

VL - 24

SP - 395

EP - 406

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -