Inhibition of Haspin Kinase Promotes Cell-Intrinsic and Extrinsic Antitumor Activity.
Animals
Azepines
/ pharmacology
CD8-Positive T-Lymphocytes
/ immunology
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Knockdown Techniques
Humans
Indoles
/ pharmacology
Interferon Type I
/ immunology
Intracellular Signaling Peptides and Proteins
/ antagonists & inhibitors
Lymphocytes, Tumor-Infiltrating
/ immunology
Melanoma
/ drug therapy
Mice
Mitogen-Activated Protein Kinase Kinases
/ antagonists & inhibitors
Protein Kinase Inhibitors
/ pharmacology
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Skin Neoplasms
/ drug therapy
Tumor Microenvironment
/ drug effects
Xenograft Model Antitumor Assays
raf Kinases
/ antagonists & inhibitors
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 02 2020
15 02 2020
Historique:
received:
27
07
2019
revised:
30
10
2019
accepted:
20
12
2019
pubmed:
29
12
2019
medline:
22
8
2020
entrez:
29
12
2019
Statut:
ppublish
Résumé
Patients with melanoma resistant to RAF/MEK inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease. New drugs that control tumor growth and favorably modulate the immune environment are therefore needed. We report that the small-molecule CX-6258 has potent activity against both RMi-sensitive (RMS) and -resistant (RMR) melanoma cell lines. Haspin kinase (HASPIN) was identified as a target of CX-6258. HASPIN inhibition resulted in reduced proliferation, frequent formation of micronuclei, recruitment of cGAS, and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In murine models, CX-6258 induced a potent cGAS-dependent type-I IFN response in tumor cells, increased IFNγ-producing CD8
Identifiants
pubmed: 31882401
pii: 0008-5472.CAN-19-2330
doi: 10.1158/0008-5472.CAN-19-2330
pmc: PMC7029677
mid: NIHMS1547612
doi:
Substances chimiques
Azepines
0
CX-6258
0
Indoles
0
Interferon Type I
0
Intracellular Signaling Peptides and Proteins
0
Protein Kinase Inhibitors
0
HASPIN protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
raf Kinases
EC 2.7.11.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
798-810Subventions
Organisme : NCI NIH HHS
ID : U54 CA225088
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA238039
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA222663
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA208008
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA207021
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA155258
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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