PMID- 30607633
OWN - NLM
STAT- MEDLINE
DCOM- 20190716
LR  - 20220727
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Print)
IS  - 0167-6806 (Linking)
VI  - 174
IP  - 3
DP  - 2019 Apr
TI  - Synergistic anti-cancer activity of CDK4/6 inhibitor palbociclib and dual mTOR 
      kinase inhibitor MLN0128 in pRb-expressing ER-negative breast cancer.
PG  - 615-625
LID - 10.1007/s10549-018-05104-9 [doi]
AB  - PURPOSE: Palbociclib is an approved cyclin-dependent kinase (CDK) 4/6 inhibitor 
      for treatment of patients with ER-positive and HER2-negative breast cancers. 
      While Retinoblastoma protein (pRb), a major substrate of CDK4/6, is a potential 
      target in triple negative breast cancer (TNBC), the usefulness of CDK4/6 
      inhibitors in this cancer has not been established. This preclinical study 
      investigated the combination effects of palbociclib and the dual mammalian target 
      of rapamycin (mTOR) kinase inhibitor MLN0128 in estrogen receptor (ER)-negative 
      breast cancer in vitro and in vivo. METHODS: The combined effects of two drugs on 
      three TNBC cell lines (MB231, MB468, and CAL148) and an ER-negative and 
      HER2-positive cell line (MB453) were investigated by MTT assay and colony 
      formation analysis. Cell cycle measurements were examined as well as changes in 
      expression of molecules related to G1/S transition and the mTOR pathway. 
      Importantly, a pRb-expressing TNBC patient-derived xenograft (PDX) model was used 
      to assess the effects of the combination in vivo. RESULTS: A combination of 
      palbociclib and MLN0128 synergistically inhibited the proliferation of 
      pRb-expressing cell lines and induced G1 cell cycle arrest. Western blot analysis 
      revealed that CDK4/6-pRb and mTOR pathways were inhibited by these treatments. In 
      pRb-expressing TNBC PDX, the combination treatment drastically suppressed tumor 
      growth compared to either the control or single drug treatments. In addition, the 
      combination treatment significantly reduced the number of Ki67-positive cells. 
      CONCLUSIONS: We revealed that palbociclib and MLN0128 had synergistic anti-cancer 
      activity in both pRb + ER-negative cell lines and a TNBC PDX model. Our results 
      indicate that such combination therapy is worthy of further investigation in a 
      clinical setting.
FAU - Yamamoto, Takuro
AU  - Yamamoto T
AD  - Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, 
      CA, 91010, USA.
FAU - Kanaya, Noriko
AU  - Kanaya N
AD  - Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, 
      CA, 91010, USA.
FAU - Somlo, George
AU  - Somlo G
AD  - Department of Medical Oncology, City of Hope Medical Center, Duarte, CA, 91010, 
      USA.
FAU - Chen, Shiuan
AU  - Chen S
AUID- ORCID: 0000-0002-4482-6926
AD  - Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, 
      CA, 91010, USA. Schen@coh.org.
LA  - eng
GR  - P30 CA033572/CA/NCI NIH HHS/United States
GR  - P30CA033572/National Cancer Institute/
PT  - Journal Article
DEP - 20190103
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Benzoxazoles)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Retinoblastoma Protein)
RN  - G9ZF61LE7G (palbociclib)
RN  - JGH0DF1U03 (sapanisertib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & 
      dosage/pharmacology
MH  - Benzoxazoles/*administration & dosage/pharmacology
MH  - Breast Neoplasms/*drug therapy/genetics
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Drug Synergism
MH  - Female
MH  - Humans
MH  - Mice
MH  - Piperazines/*administration & dosage/pharmacology
MH  - Protein Kinase Inhibitors/*administration & dosage/pharmacology
MH  - Pyridines/*administration & dosage/pharmacology
MH  - Pyrimidines/*administration & dosage/pharmacology
MH  - Receptors, Estrogen/metabolism
MH  - Retinoblastoma Protein/genetics
MH  - Xenograft Model Antitumor Assays
PMC - PMC6452902
MID - NIHMS1524922
OTO - NOTNLM
OT  - CDK 4/6 inhibitor
OT  - MLN0128
OT  - Palbociclib
OT  - Retinoblastoma protein (pRb)
OT  - Triple negative breast cancer (TNBC)
OT  - mTOR inhibitor
COIS- Conflict of interest The authors declare that they have no competing interests.
EDAT- 2019/01/05 06:00
MHDA- 2019/07/17 06:00
PMCR- 2020/04/01
CRDT- 2019/01/05 06:00
PHST- 2018/08/13 00:00 [received]
PHST- 2018/12/14 00:00 [accepted]
PHST- 2019/01/05 06:00 [pubmed]
PHST- 2019/07/17 06:00 [medline]
PHST- 2019/01/05 06:00 [entrez]
PHST- 2020/04/01 00:00 [pmc-release]
AID - 10.1007/s10549-018-05104-9 [pii]
AID - 10.1007/s10549-018-05104-9 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2019 Apr;174(3):615-625. doi: 
      10.1007/s10549-018-05104-9. Epub 2019 Jan 3.