m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT02244
 [1], [2]
DNA methylation DNMT3A METTL14 Direct Inhibition m6A modification SLC7A11 SLC7A11 METTL14 Methylation : m6A sites
m6A Modification:
m6A Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
m6A Target Cystine/glutamate transporter (SLC7A11)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type DNA methylation (DNAMeth)
Epigenetic Regulator Cysteine methyltransferase DNMT3A (DNMT3A) WRITER View Details
Regulated Target Methyltransferase-like protein 14 (METTL14) View Details
Crosstalk Relationship DNA methylation  →  m6A Inhibition
Crosstalk Mechanism DNA methylation directly impacts m6A modification through modulating the expression level of m6A regulator
Crosstalk Summary lncRNA UCA1 recruited DNA methyltransferase (DNMT1, DNMT3A, and DNMT3B) to the METTL14 promoter region to inhibit METTL14 expression in breast cancer. m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3beta and activates beta-catenin/TCF4-Cystine/glutamate transporter (SLC7A11)/FPN1 signaling to drive anti-HER2 resistance. Knockdown of METTL14 significantly increased the expression level of FGFR4 in HER2-positive breast cancer cells. FGFR4 reduced the sensitivity of HER2-positive breast cancer to trastuzumab plus pertuzumab or tucatinib. These results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Responsed Drug Tucatinib
 Drug Info 
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model
 MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
SUM159PT Breast pleomorphic carcinoma Homo sapiens CVCL_5423
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
In-vivo Model Luciferase-labeled rSKBR3 and MDA-MB-361 cells (1 × 107 cells) mixed with 1:1 Matrigel (Corning, 356237) were subcutaneously injected into the fat pads of mice. After a tumor was palpable, the mice were randomized into four groups (five mice per group), and they were treated with vehicle, trastuzumab (20 mg/kg, intraperitoneal administration), roblitinib (30 mg/kg, oral administration), or a combination of both drugs.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Cysteine methyltransferase DNMT3A (DNMT3A) 8 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name PMID27376512-Compound-Figure3CN Patented [3]
MOA Inhibitor
Activity EC50 = 1100 nM
External Link
CID: 117968550
TTD: D02VTV
 Compound Name PMID27376512-Compound-Figure3CG Patented [3]
MOA Inhibitor
Activity EC50 = 2400 nM
External Link
CID: 117967861
TTD: D03LZO
 Compound Name PMID27376512-Compound-Figure3CM Patented [3]
MOA Inhibitor
Activity EC50 = 1100 nM
External Link
CID: 117976053
TTD: D0F8AB
 Compound Name PMID27376512-Compound-Figure2aExample1 Patented [3]
MOA Inhibitor
Activity IC50 = 3000 nM
External Link
CID: 71521835
TTD: D01LUJ
 Compound Name PMID27376512-Compound-MTC-424 Patented [3]
MOA Inhibitor
Activity IC50 = 1940 nM
External Link
TTD: D02WRM
 Compound Name PMID27376512-Compound-MTC-427 Patented [3]
MOA Inhibitor
Activity IC50 = 295 nM
External Link
TTD: D0HA0J
 Compound Name PMID27376512-Compound-MTC-422 Patented [3]
MOA Inhibitor
Activity IC50 = 1430 nM
External Link
TTD: D0QY0N
 Compound Name PMID27376512-Compound-MTC-423 Patented [3]
MOA Inhibitor
Activity IC50 = 363 nM
External Link
TTD: D0W9VZ
Cystine/glutamate transporter (SLC7A11) 1 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name SXC-2023 Phase 2 [4]
MOA Activator
External Link
TTD: D1KO3P
2C60: Breast cancer 2 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Entrectinib Approved [5]
Synonyms
1108743-60-7; RXDX-101; UNII-L5ORF0AN1I; Entrectinib (RXDX-101); L5ORF0AN1I; Benzamide, N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2H-pyran-4-yl)amino]-; Benzamide, N-(5-((3,5-difluorophenyl)methyl)-1H-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-((tetrahydro-2H-pyran-4-yl)amino)-; Entrectinib [USAN:INN]; YMX; Kinome_2659; Entrectinib(rxdx-101); Entrectinib (USAN/INN); SCHEMBL3512601; GTPL8290; CHEMBL1983268; KS-00000TSK
    Click to Show/Hide
External Link
CID: 25141092
TTD: D0O0LS
DrugBank: DB11986
 Compound Name Everolimus Approved [6]
External Link
CID: 6442177
TTD: D09ZSC
DrugBank: DB01590
References
Ref 1 LncRNA UCA1 promotes SOX12 expression in breast cancer by regulating m(6)A modification of miR-375 by METTL14 through DNA methylation. Cancer Gene Ther. 2022 Jul;29(7):1043-1055. doi: 10.1038/s41417-021-00390-w. Epub 2022 Jan 13.
Ref 2 N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nat Commun. 2022 May 13;13(1):2672. doi: 10.1038/s41467-022-30217-7.
Ref 3 DNA methyltransferase inhibitors: an updated patent review (2012-2015). Expert Opin Ther Pat. 2016 Sep;26(9):1017-30. doi: 10.1080/13543776.2016.1209488. Epub 2016 Jul 18.
Ref 4 Clinical pipeline report, company report or official report of Promentis Pharmaceuticals.
Ref 5 Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372... Cancer Discov. 2017 Apr;7(4):400-409.
Ref 6 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015