Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma.
Animals
Antineoplastic Agents
/ pharmacology
Benzeneacetamides
/ pharmacology
Cell Line, Tumor
Cyclin D1
/ genetics
Cyclin-Dependent Kinase 4
/ antagonists & inhibitors
Cyclin-Dependent Kinase 6
/ antagonists & inhibitors
Drug Resistance, Neoplasm
/ drug effects
Drug Synergism
Energy Metabolism
/ drug effects
Esophageal Neoplasms
/ drug therapy
Esophageal Squamous Cell Carcinoma
/ drug therapy
F-Box Proteins
/ genetics
Gene Expression Regulation, Neoplastic
Glutaminase
/ antagonists & inhibitors
Glutamine
/ antagonists & inhibitors
Humans
Hypoglycemic Agents
/ pharmacology
Male
Mechanistic Target of Rapamycin Complex 1
/ genetics
Metformin
/ pharmacology
Mice
Molecular Targeted Therapy
Phenformin
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Retinoblastoma Protein
/ genetics
Signal Transduction
Thiadiazoles
/ pharmacology
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 03 2019
21 03 2019
Historique:
received:
19
02
2018
accepted:
20
02
2019
entrez:
23
3
2019
pubmed:
23
3
2019
medline:
5
4
2019
Statut:
epublish
Résumé
The dysregulation of Fbxo4-cyclin D1 axis occurs at high frequency in esophageal squamous cell carcinoma (ESCC), where it promotes ESCC development and progression. However, defining a therapeutic vulnerability that results from this dysregulation has remained elusive. Here we demonstrate that Rb and mTORC1 contribute to Gln-addiction upon the dysregulation of the Fbxo4-cyclin D1 axis, which leads to the reprogramming of cellular metabolism. This reprogramming is characterized by reduced energy production and increased sensitivity of ESCC cells to combined treatment with CB-839 (glutaminase 1 inhibitor) plus metformin/phenformin. Of additional importance, this combined treatment has potent efficacy in ESCC cells with acquired resistance to CDK4/6 inhibitors in vitro and in xenograft tumors. Our findings reveal a molecular basis for cancer therapy through targeting glutaminolysis and mitochondrial respiration in ESCC with dysregulated Fbxo4-cyclin D1 axis as well as cancers resistant to CDK4/6 inhibitors.
Identifiants
pubmed: 30899002
doi: 10.1038/s41467-019-09179-w
pii: 10.1038/s41467-019-09179-w
pmc: PMC6428878
doi:
Substances chimiques
Antineoplastic Agents
0
Benzeneacetamides
0
CB-839
0
CCND1 protein, human
0
F-Box Proteins
0
FBXO4 protein, human
0
Hypoglycemic Agents
0
Protein Kinase Inhibitors
0
Retinoblastoma Protein
0
Thiadiazoles
0
Glutamine
0RH81L854J
Cyclin D1
136601-57-5
Metformin
9100L32L2N
Phenformin
DD5K7529CE
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
CDK4 protein, human
EC 2.7.11.22
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Glutaminase
EC 3.5.1.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1296Subventions
Organisme : NIH HHS
ID : T32 DE017551
Pays : United States
Organisme : NIH HHS
ID : P01 CA098101
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA098101
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA093237
Pays : United States
Organisme : NIDCR NIH HHS
ID : T32 DE017551
Pays : United States
Références
Genes Dev. 2007 Nov 15;21(22):2908-22
pubmed: 18006686
Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7
pubmed: 19033189
Cancer Discov. 2015 Mar;5(3):288-303
pubmed: 25582697
Cancer Res. 2016 May 15;76(10):2990-3002
pubmed: 26988987
Nat Commun. 2017 Nov 16;8(1):1534
pubmed: 29142209
EMBO J. 2017 Feb 15;36(4):397-408
pubmed: 28096180
Cancer Res. 2015 May 1;75(9):1782-8
pubmed: 25855379
Cancer Res. 2005 Dec 15;65(24):11354-60
pubmed: 16357142
Ann Oncol. 2018 Mar 1;29(3):640-645
pubmed: 29236940
BMC Genomics. 2010 Oct 18;11:576
pubmed: 20955586
Cancer Cell. 2008 Jul 8;14(1):68-78
pubmed: 18598945
Cancer Cell. 2012 Nov 13;22(5):631-44
pubmed: 23153536
Oncogene. 2010 Jan 21;29(3):313-24
pubmed: 19881548
Gut. 2017 Jul;66(7):1286-1296
pubmed: 27849562
Nat Rev Cancer. 2015 Jul;15(7):397-408
pubmed: 26105537
Cell. 2012 Apr 13;149(2):274-93
pubmed: 22500797
Mol Cell. 2010 May 28;38(4):487-99
pubmed: 20513425
Cancer Cell. 2016 Mar 14;29(3):255-269
pubmed: 26977878
Cancer Cell. 2010 Sep 14;18(3):207-19
pubmed: 20832749
Cancer Cell. 2012 Oct 16;22(4):438-51
pubmed: 23079655
J Cell Biochem. 2014 Mar;115(3):498-509
pubmed: 24122876
Nature. 2016 Aug 11;536(7615):229-33
pubmed: 27487210
Genes Dev. 2013 Jan 15;27(2):182-96
pubmed: 23322302
J Cancer Res Clin Oncol. 1993;119(8):441-9
pubmed: 8509434
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Clin Cancer Res. 2011 Jul 1;17(13):4513-22
pubmed: 21593195
Nat Commun. 2017 Sep 12;8(1):524
pubmed: 28900112
Nat Rev Mol Cell Biol. 2004 Sep;5(9):739-51
pubmed: 15340381
Nature. 2017 Jan 12;541(7636):169-175
pubmed: 28052061
Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):E5328-36
pubmed: 27559084
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9298-E9307
pubmed: 30224477
Crit Rev Biochem Mol Biol. 2013 Nov-Dec;48(6):609-19
pubmed: 24099138
Cancer. 1995 Aug 15;76(4):541-9
pubmed: 8625145
Cancer Cell. 2015 Mar 9;27(3):354-69
pubmed: 25759021
Genes Dev. 1997 Apr 15;11(8):957-72
pubmed: 9136925
Cell Cycle. 2012 Oct 1;11(19):3679-90
pubmed: 22935705
Cancer Res. 2007 Sep 1;67(17):7996-8001
pubmed: 17804709
Cell Metab. 2017 Nov 7;26(5):778-787.e5
pubmed: 28988825
Cancer Cell. 2010 Oct 19;18(4):329-40
pubmed: 20951943
Mol Cell Biol. 2008 Dec;28(23):7245-58
pubmed: 18809569
EMBO J. 2017 May 15;36(10):1302-1315
pubmed: 28420743
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2945-9
pubmed: 8159685
Cancer Biol Ther. 2015;16(5):750-5
pubmed: 25801820
Mol Cell. 2015 Jul 16;59(2):298-308
pubmed: 26166707
Mol Cell Biol. 2013 Nov;33(22):4422-33
pubmed: 24019069
Oncogene. 2010 Jul 15;29(28):4018-32
pubmed: 20473330
Lancet. 2013 Feb 2;381(9864):400-12
pubmed: 23374478
Methods Mol Biol. 2003;222:131-45
pubmed: 12710684
Br J Pharmacol. 2017 Aug;174(15):2427-2443
pubmed: 28444744
Crit Rev Eukaryot Gene Expr. 2012;22(1):17-35
pubmed: 22339657
Nature. 2014 Jun 26;510(7506):547-51
pubmed: 24870244
Cancer Cell. 2018 May 14;33(5):905-921.e5
pubmed: 29763624
Drugs. 2015 Apr;75(5):543-51
pubmed: 25792301
Cancer Res. 2013 Jul 15;73(14):4429-38
pubmed: 23687346
J Mol Med (Berl). 2016 Dec;94(12):1313-1326
pubmed: 27695879
N Engl J Med. 2014 Dec 25;371(26):2499-509
pubmed: 25539106
J Clin Oncol. 2017 Sep 1;35(25):2949-2959
pubmed: 28580868
Oncotarget. 2016 Sep 13;7(42):68012-68022
pubmed: 27634906
Proc Natl Acad Sci U S A. 2012 May 15;109(20):7705-10
pubmed: 22538822
Mol Syst Biol. 2017 Oct 4;13(10):940
pubmed: 28978620
J Cell Biol. 1994 May;125(3):625-38
pubmed: 8175885
Nature. 2009 Apr 9;458(7239):762-5
pubmed: 19219026
J Clin Oncol. 2017 Sep 1;35(25):2875-2884
pubmed: 28580882
Mol Cell. 2006 Nov 3;24(3):355-66
pubmed: 17081987