PMID- 34115902
OWN - NLM
STAT- MEDLINE
DCOM- 20220203
LR  - 20220203
IS  - 1365-2230 (Electronic)
IS  - 0307-6938 (Linking)
VI  - 46
IP  - 8
DP  - 2021 Dec
TI  - The novel AKT inhibitor afuresertib suppresses human Merkel cell carcinoma MKL-1 
      cell growth.
PG  - 1551-1554
LID - 10.1111/ced.14798 [doi]
AB  - Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the 
      skin, which has an exceedingly poor prognosis. The AKT/mammalian target of 
      rapamycin (mTOR) signalling pathway, which plays a pivotal role in the modulation 
      of protein synthesis and cell survival, has been shown to be extremely important 
      for Merkel cell carcinogenesis. In the current study, we found that AKT has 
      important regulatory functions in MCC cells and that inhibition of AKT with the 
      novel ATP-competitive AKT inhibitor, afuresertib, has widespread effects on 
      proliferative pathways. In particular, we found that treatment of MCC cells with 
      afuresertib led to deactivation of mTOR and glycogen synthase kinase 3 pathway 
      proteins while increasing activation of proapoptotic pathways through the 
      upregulation of p16 expression and phosphomodulation of the B-cell 
      lymphoma-2-associated death promoter. Overall, afuresertib treatment led to 
      significant and robust inhibition of MCC cell proliferation, thus raising 
      intriguing questions regarding the potential efficacy of AKT inhibition for the 
      future clinical management of MCC.
CI  - (c) 2021 British Association of Dermatologists.
FAU - Wu, J H
AU  - Wu JH
AUID- ORCID: 0000-0001-5841-0414
AD  - Department of Dermatology, McGovern Medical School at The University of Texas 
      Health Science Center, Houston, TX, USA.
AD  - Ronald O. Perelman Department of Dermatology, New York University, New York, NY, 
      USA.
FAU - Limmer, A L
AU  - Limmer AL
AUID- ORCID: 0000-0001-6198-5921
AD  - Department of Dermatology, McGovern Medical School at The University of Texas 
      Health Science Center, Houston, TX, USA.
FAU - Narayanan, D
AU  - Narayanan D
AUID- ORCID: 0000-0002-7137-8663
AD  - Department of Dermatology, McGovern Medical School at The University of Texas 
      Health Science Center, Houston, TX, USA.
FAU - Doan, H Q
AU  - Doan HQ
AD  - Department of Dermatology, McGovern Medical School at The University of Texas 
      Health Science Center, Houston, TX, USA.
AD  - Department of Dermatology, Division of Internal Medicine, The University of Texas 
      MD Anderson Cancer Center, Houston, TX, USA.
FAU - Simonette, R A
AU  - Simonette RA
AD  - Department of Dermatology, McGovern Medical School at The University of Texas 
      Health Science Center, Houston, TX, USA.
FAU - Rady, P L
AU  - Rady PL
AD  - Department of Dermatology, McGovern Medical School at The University of Texas 
      Health Science Center, Houston, TX, USA.
FAU - Tyring, S K
AU  - Tyring SK
AD  - Department of Dermatology, McGovern Medical School at The University of Texas 
      Health Science Center, Houston, TX, USA.
LA  - eng
PT  - Journal Article
DEP - 20210826
PL  - England
TA  - Clin Exp Dermatol
JT  - Clinical and experimental dermatology
JID - 7606847
RN  - 0 (Antineoplastic Agents)
RN  - 0 (MRTFA protein, human)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Pyrazoles)
RN  - 0 (Thiophenes)
RN  - 0 (Trans-Activators)
RN  - 8739X25QI3 (afuresertib)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Antineoplastic Agents/*therapeutic use
MH  - Carcinoma, Merkel Cell/*drug therapy/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Genes, p16/drug effects
MH  - Glycogen Synthase Kinase 3/drug effects/metabolism
MH  - Humans
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors
MH  - Proto-Oncogene Proteins c-bcl-2/drug effects/metabolism
MH  - Pyrazoles/*therapeutic use
MH  - Signal Transduction
MH  - Skin Neoplasms/*drug therapy/pathology
MH  - TOR Serine-Threonine Kinases/drug effects/metabolism
MH  - Thiophenes/*therapeutic use
MH  - Trans-Activators/*antagonists & inhibitors
MH  - Up-Regulation
EDAT- 2021/06/12 06:00
MHDA- 2022/02/04 06:00
CRDT- 2021/06/11 17:27
PHST- 2021/06/07 00:00 [revised]
PHST- 2021/02/07 00:00 [received]
PHST- 2021/06/08 00:00 [accepted]
PHST- 2021/06/12 06:00 [pubmed]
PHST- 2022/02/04 06:00 [medline]
PHST- 2021/06/11 17:27 [entrez]
AID - 10.1111/ced.14798 [doi]
PST - ppublish
SO  - Clin Exp Dermatol. 2021 Dec;46(8):1551-1554. doi: 10.1111/ced.14798. Epub 2021 
      Aug 26.