Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.
Antineoplastic Agents
/ pharmacology
Apoptosis
Carcinoma, Squamous Cell
/ diagnosis
Cell Cycle Proteins
/ genetics
Epidermolysis Bullosa Dystrophica
/ complications
Gene Knockdown Techniques
Genes, Recessive
Glycine
/ analogs & derivatives
Humans
Keratinocytes
/ drug effects
Molecular Targeted Therapy
Protein Serine-Threonine Kinases
/ genetics
Proto-Oncogene Proteins
/ genetics
RNA, Messenger
RNA, Small Interfering
Skin Neoplasms
/ diagnosis
Sulfones
/ pharmacology
Polo-Like Kinase 1
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
15
08
2018
revised:
11
01
2019
accepted:
21
02
2019
pubmed:
9
3
2019
medline:
7
7
2020
entrez:
9
3
2019
Statut:
ppublish
Résumé
Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.
Identifiants
pubmed: 30846478
pii: 1078-0432.CCR-18-2661
doi: 10.1158/1078-0432.CCR-18-2661
pmc: PMC8185613
mid: NIHMS1701557
doi:
Substances chimiques
Antineoplastic Agents
0
Cell Cycle Proteins
0
Proto-Oncogene Proteins
0
RNA, Messenger
0
RNA, Small Interfering
0
Sulfones
0
ON 01910
67DOW7F9GL
Protein Serine-Threonine Kinases
EC 2.7.11.1
Glycine
TE7660XO1C
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3384-3391Subventions
Organisme : NCI NIH HHS
ID : P30 CA056036
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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