SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
Animals
Apoptosis
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Proliferation
Chromatin
/ genetics
Drug Resistance, Neoplasm
Female
Histocompatibility Antigens
/ genetics
Histone Deacetylases
/ chemistry
Histone-Lysine N-Methyltransferase
/ antagonists & inhibitors
Humans
MAP Kinase Kinase 1
/ antagonists & inhibitors
MAP Kinase Kinase 2
/ antagonists & inhibitors
Methyltransferases
/ antagonists & inhibitors
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
Pancreatic Neoplasms
/ drug therapy
Protein Kinase Inhibitors
/ pharmacology
Pyridones
/ pharmacology
Pyrimidinones
/ pharmacology
Small Molecule Libraries
/ pharmacology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
KRAS
MEK inhibition
RAS signaling
SETD5
lysine methylation
pancreatic cancer
protein methylation
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
08 06 2020
08 06 2020
Historique:
received:
30
12
2019
revised:
11
03
2020
accepted:
22
04
2020
pubmed:
23
5
2020
medline:
4
11
2020
entrez:
23
5
2020
Statut:
ppublish
Résumé
Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.
Identifiants
pubmed: 32442403
pii: S1535-6108(20)30213-0
doi: 10.1016/j.ccell.2020.04.014
pmc: PMC8187079
mid: NIHMS1676917
pii:
doi:
Substances chimiques
Chromatin
0
Histocompatibility Antigens
0
Protein Kinase Inhibitors
0
Pyridones
0
Pyrimidinones
0
Small Molecule Libraries
0
trametinib
33E86K87QN
Methyltransferases
EC 2.1.1.-
SETD5 protein, human
EC 2.1.1.-
EHMT2 protein, human
EC 2.1.1.43
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
MAP2K2 protein, human
EC 2.7.1.-
MAP Kinase Kinase 1
EC 2.7.12.2
MAP Kinase Kinase 2
EC 2.7.12.2
MAP2K1 protein, human
EC 2.7.12.2
Histone Deacetylases
EC 3.5.1.98
histone deacetylase 3
EC 3.5.1.98
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
834-849.e13Subventions
Organisme : NICHD NIH HHS
ID : DP2 HD084069
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA255936
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236949
Pays : United States
Organisme : NIGMS NIH HHS
ID : R44 GM116584
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declarations of Interests O.G. is a co-founder of EpiCyphe and Athelas Therapeutics. M.C.K., M.J.M., M.A.C., and S.A.H. are employees and shareholders of EpiCypher.
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