PMID- 29079660
OWN - NLM
STAT- MEDLINE
DCOM- 20190724
LR  - 20220727
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 24
IP  - 2
DP  - 2018 Jan 15
TI  - Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR(+)/HER2(+) Breast Cancer 
      Patient-Derived Xenografts to Trastuzumab or Fulvestrant.
PG  - 395-406
LID - 10.1158/1078-0432.CCR-17-1983 [doi]
AB  - 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 ERalpha 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. (c)2017 AACR.
CI  - (c)2017 American Association for Cancer Research.
FAU - Hsu, Pei-Yin
AU  - Hsu PY
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California.
FAU - Wu, Victoria Shang
AU  - Wu VS
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California.
FAU - Kanaya, Noriko
AU  - Kanaya N
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California.
FAU - Petrossian, Karineh
AU  - Petrossian K
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California.
FAU - Hsu, Hang-Kai
AU  - Hsu HK
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California.
FAU - Nguyen, Duc
AU  - Nguyen D
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California.
FAU - Schmolze, Daniel
AU  - Schmolze D
AD  - Department of Pathology, City of Hope Medical Center, Duarte, California.
FAU - Kai, Masaya
AU  - Kai M
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California.
FAU - Liu, Chun-Yu
AU  - Liu CY
AD  - Department of Oncology, School of Medicine, National Yang-Ming University, 
      Taipei, Taiwan.
FAU - Lu, Hannah
AU  - Lu H
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California.
FAU - Chu, Peiguo
AU  - Chu P
AD  - Department of Pathology, City of Hope Medical Center, Duarte, California.
FAU - Vito, Courtney A
AU  - Vito CA
AD  - Department of Surgery, City of Hope Medical Center, Duarte, California.
FAU - Kruper, Laura
AU  - Kruper L
AD  - Department of Surgery, City of Hope Medical Center, Duarte, California.
FAU - Mortimer, Joanne
AU  - Mortimer J
AD  - Department of Medical Oncology and Therapeutic Research, City of Hope Medical 
      Center, Duarte, California.
FAU - Chen, Shiuan
AU  - Chen S
AD  - Department of Cancer Biology, Beckman Research Institute of the City of Hope, 
      Duarte, California. schen@coh.org.
LA  - eng
GR  - P30 CA033572/CA/NCI NIH HHS/United States
GR  - R01 CA044735/CA/NCI NIH HHS/United States
GR  - R01 ES008258/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171027
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Benzoxazoles)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Estrogens)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 22X328QOC4 (Fulvestrant)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - JGH0DF1U03 (sapanisertib)
RN  - P188ANX8CK (Trastuzumab)
MH  - Animals
MH  - Benzoxazoles/*pharmacology
MH  - Biomarkers, Tumor
MH  - Breast Neoplasms/drug therapy/*metabolism/mortality/pathology
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Estrogens/metabolism
MH  - Female
MH  - Fulvestrant/*pharmacology
MH  - Humans
MH  - Immunohistochemistry
MH  - Mice
MH  - Mice, Knockout
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Pyrimidines/*pharmacology
MH  - Receptor, ErbB-2/*antagonists & inhibitors
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Transcriptome
MH  - Trastuzumab/*pharmacology
MH  - Treatment Outcome
MH  - Xenograft Model Antitumor Assays
PMC - PMC8820221
MID - NIHMS1772810
COIS- Conflicts of interest: The authors declare no potential conflicts of interest.
EDAT- 2017/10/29 06:00
MHDA- 2019/07/25 06:00
PMCR- 2022/02/07
CRDT- 2017/10/29 06:00
PHST- 2017/07/10 00:00 [received]
PHST- 2017/09/24 00:00 [revised]
PHST- 2017/10/23 00:00 [accepted]
PHST- 2017/10/29 06:00 [pubmed]
PHST- 2019/07/25 06:00 [medline]
PHST- 2017/10/29 06:00 [entrez]
PHST- 2022/02/07 00:00 [pmc-release]
AID - 1078-0432.CCR-17-1983 [pii]
AID - 10.1158/1078-0432.CCR-17-1983 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2018 Jan 15;24(2):395-406. doi: 10.1158/1078-0432.CCR-17-1983. 
      Epub 2017 Oct 27.