m6A-centered Drug Response Information

General Information of the Drug (ID: M6ADRUG0092)
Name
Trastuzumab
Status Approved [1]
TTD Drug ID
D04WFL
DrugBank ID
DB00072
Full List of m6A Targets Related to This Drug
Catenin beta-1 (CTNNB1/Beta-catenin)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3beta and activates Catenin beta-1 (CTNNB1/Beta-catenin)/TCF4-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 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
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.
Cystine/glutamate transporter (SLC7A11)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary 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 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
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.
Fibroblast growth factor receptor 4 (FGFR4)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary m6A-hypomethylation regulated Fibroblast growth factor receptor 4 (FGFR4) phosphorylates GSK-3beta and activates beta-catenin/TCF4-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 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
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.
Glycogen synthase kinase-3 beta (GSK3Beta/GSK3B)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary m6A-hypomethylation regulated FGFR4 phosphorylates Glycogen synthase kinase-3 beta (GSK3Beta/GSK3B) and activates beta-catenin/TCF4-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 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
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.
Solute carrier family 40 member 1 (FPN1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3beta and activates beta-catenin/TCF4-SLC7A11/Solute carrier family 40 member 1 (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 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
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.
References
Ref 1 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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.