m6A-centered Drug Response Information

General Information of the Drug (ID: M6ADRUG0030)
Name
Gefitinib
Synonyms
Iressa; ZD1839; Irressat; gefitinib (zd1839); N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine; ZD 1839; ZD-1839; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine; N-(3-Chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine; UNII-S65743JHBS; CCRIS 9011; CHEMBL939; 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4
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Status Approved [1]
Structure
Formula
C22H24ClFN4O3
InChI
InChI=1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
InChIKey
XGALLCVXEZPNRQ-UHFFFAOYSA-N
PubChem CID
123631
TTD Drug ID
D01RYO
DrugBank ID
DB00317
Full List of m6A Targets Related to This Drug
ATP-binding cassette sub-family C member 10 (ABCC10)
 Target Info 
In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary Not only FTO knockdown enhanced the gefitinib sensitivity of GR cells but also FTO reduction in donor exosomes alleviated the acquired resistance of recipient non-small cell lung cancer PC9 cells. FTO/YTHDF2/ATP-binding cassette sub-family C member 10 (ABCC10) axis played a role in intercellular transmission of GR cell-derived exosome-mediated gefitinib resistance.
Responsed Disease Non-small-cell lung carcinoma ICD-11: 2C25.Y
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Up regulation
Pathway Response ABC transporters hsa02010
In-vitro Model PC-9 Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 Lung adenocarcinoma Homo sapiens CVCL_1511
In-vivo Model Mice were randomized into three groups (n = 7/group), 1 × 107 PC9 cells absorbed exosomes were subcutaneously injected into the Bilateral groin of mice. Treatment began 1 week following injection, the mice were intraperitoneally injected with gefitinib (30 mg/kg/day).
Experiment 2 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary Not only FTO knockdown enhanced the gefitinib sensitivity of GR cells but also FTO reduction in donor exosomes alleviated the acquired resistance of recipient non-small cell lung cancer PC9 cells. FTO/YTHDF2/ATP-binding cassette sub-family C member 10 (ABCC10) axis played a role in intercellular transmission of GR cell-derived exosome-mediated gefitinib resistance.
Responsed Disease Non-small-cell lung carcinoma ICD-11: 2C25.Y
 Disease Info 
Target Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 Regulator Info 
Target Regulation Down regulation
Pathway Response ABC transporters hsa02010
In-vitro Model PC-9 Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 Lung adenocarcinoma Homo sapiens CVCL_1511
In-vivo Model Mice were randomized into three groups (n = 7/group), 1 × 107 PC9 cells absorbed exosomes were subcutaneously injected into the Bilateral groin of mice. Treatment began 1 week following injection, the mice were intraperitoneally injected with gefitinib (30 mg/kg/day).
Autophagy protein 5 (ATG5)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary METTL3 could positively regulate the autophagy by targeting the autophagy-related genes such as Autophagy protein 5 (ATG5), ATG7, LC3B, and SQSTM1. beta-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and LC3B-II. beta-elemene could reverse gefitinib resistance in non-small cell lung cancer cells by inhibiting cell autophagy process in a manner of chloroquine. METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by beta-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.
Responsed Disease Non-small-cell lung carcinoma ICD-11: 2C25.Y
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Autophagy hsa04140
Cell Process Autophagic lysosome acidification
In-vitro Model Gefitinib-resistant cell line HCC827GR (Gefitinib-resistant HCC827 cell line)
Gefitinib-resistant cell line PC9GR (Gefitinib-resistant PC9 cell line)
HCC827 Lung adenocarcinoma Homo sapiens CVCL_2063
PC-9 Lung adenocarcinoma Homo sapiens CVCL_B260
In-vivo Model NSCLC gefitinib-resistant cells (5 × 106 cells in 100 uL PBS) were injected subcutaneously into the lateral surface of the left abdomen of 6-week-old female BALB/c nude mice (at least five mice per group to ensure accuracy).
Hepatocyte growth factor receptor (c-Met/MET)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [4]
Response Summary METTL3 combines with Hepatocyte growth factor receptor (c-Met/MET) and causes the PI3K/AKT signalling pathway to be manipulated, which affects the sensitivity of lung cancer cells to gefitinib. METTL3 knockdown promotes apoptosis and inhibits proliferation of lung cancer cells.
Responsed Disease Lung cancer ICD-11: 2C25
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Pathway Response PI3K-Akt signaling pathway hsa04151
In-vitro Model PC-9 Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H3255 Lung adenocarcinoma Homo sapiens CVCL_6831
Homeobox protein Hox-A1 (HOXA1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [5]
Response Summary m6A methyltransferase KIAA1429 was highly expressed in gefitinib-resistant NSCLC cells (PC9-GR), tissues, and closely related to unfavorable survival. KIAA1429 plays essential oncogenic roles in NSCLC gefitinib resistance, which provided a feasible therapeutic target for NSCLC.
Responsed Disease Non-small-cell lung carcinoma ICD-11: 2C25.Y
 Disease Info 
Target Regulator Protein virilizer homolog (VIRMA) WRITER
 Regulator Info 
Target Regulation Up regulation
In-vitro Model Gefitinib-resistant cell line PC9GR (Gefitinib-resistant PC9 cell line)
PC-9 Lung adenocarcinoma Homo sapiens CVCL_B260
NHBE (Normal bronchial epithelial cells)
In-vivo Model PC9-GR cells stably infected with KIAA1429-targeting shRNA and control were suspended in 100 uL of PBS with Matrigel matrix (BD Biosciences). Then, cells were injected into one of the flanks of BALB/c nude mice.
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B/LC3B-II)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary METTL3 could positively regulate the autophagy by targeting the autophagy-related genes such as ATG5, ATG7, LC3B, and SQSTM1. beta-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B/LC3B-II). beta-elemene could reverse gefitinib resistance in non-small cell lung cancer cells by inhibiting cell autophagy process in a manner of chloroquine. METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by beta-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.
Responsed Disease Non-small-cell lung carcinoma ICD-11: 2C25.Y
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Autophagy hsa04140
Cell Process Autophagic lysosome acidification
In-vitro Model Gefitinib-resistant cell line HCC827GR (Gefitinib-resistant HCC827 cell line)
Gefitinib-resistant cell line PC9GR (Gefitinib-resistant PC9 cell line)
HCC827 Lung adenocarcinoma Homo sapiens CVCL_2063
PC-9 Lung adenocarcinoma Homo sapiens CVCL_B260
In-vivo Model NSCLC gefitinib-resistant cells (5 × 106 cells in 100 uL PBS) were injected subcutaneously into the lateral surface of the left abdomen of 6-week-old female BALB/c nude mice (at least five mice per group to ensure accuracy).
Sequestosome-1 (SQSTM1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary METTL3 could positively regulate the autophagy by targeting the autophagy-related genes such as ATG5, ATG7, LC3B, and Sequestosome-1 (SQSTM1). beta-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and LC3B-II. beta-elemene could reverse gefitinib resistance in non-small cell lung cancer cells by inhibiting cell autophagy process in a manner of chloroquine. METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by beta-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.
Responsed Disease Non-small-cell lung carcinoma ICD-11: 2C25.Y
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Autophagy hsa04140
Cell Process Autophagic lysosome acidification
In-vitro Model Gefitinib-resistant cell line HCC827GR (Gefitinib-resistant HCC827 cell line)
Gefitinib-resistant cell line PC9GR (Gefitinib-resistant PC9 cell line)
HCC827 Lung adenocarcinoma Homo sapiens CVCL_2063
PC-9 Lung adenocarcinoma Homo sapiens CVCL_B260
In-vivo Model NSCLC gefitinib-resistant cells (5 × 106 cells in 100 uL PBS) were injected subcutaneously into the lateral surface of the left abdomen of 6-week-old female BALB/c nude mice (at least five mice per group to ensure accuracy).
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary METTL3 could positively regulate the autophagy by targeting the autophagy-related genes such as ATG5, Ubiquitin-like modifier-activating enzyme ATG7 (ATG7), LC3B, and SQSTM1. beta-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and LC3B-II. beta-elemene could reverse gefitinib resistance in non-small cell lung cancer cells by inhibiting cell autophagy process in a manner of chloroquine. METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by beta-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.
Responsed Disease Non-small-cell lung carcinoma ICD-11: 2C25.Y
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Autophagy hsa04140
Cell Process Autophagic lysosome acidification
In-vitro Model Gefitinib-resistant cell line HCC827GR (Gefitinib-resistant HCC827 cell line)
Gefitinib-resistant cell line PC9GR (Gefitinib-resistant PC9 cell line)
HCC827 Lung adenocarcinoma Homo sapiens CVCL_2063
PC-9 Lung adenocarcinoma Homo sapiens CVCL_B260
In-vivo Model NSCLC gefitinib-resistant cells (5 × 106 cells in 100 uL PBS) were injected subcutaneously into the lateral surface of the left abdomen of 6-week-old female BALB/c nude mice (at least five mice per group to ensure accuracy).
Circ_ASK1
 Target Info 
In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [6]
Response Summary Increased YTHDF2-mediated endoribonucleolytic cleavage of m6A-modified Circ_ASK1 accounts for its downregulation in gefitinib-resistant cells. Either METTL3 silencing or YTHDF2 silencing suppressed the decay of circASK1 in HCC827-GR cells. This study provides a novel therapeutic target to overcome gefitinib resistance in LUAD patients.
Responsed Disease Lung adenocarcinoma ICD-11: 2C25.0
 Disease Info 
Target Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 Regulator Info 
Target Regulation Down regulation
Cell Process Cell apoptosis
In-vitro Model SPC-A1 Endocervical adenocarcinoma Homo sapiens CVCL_6955
SK-LU-1 Lung adenocarcinoma Homo sapiens CVCL_0629
NCI-H1993 Lung adenocarcinoma Homo sapiens CVCL_1512
NCI-H1975 Lung adenocarcinoma Homo sapiens CVCL_1511
NCI-H1650 Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1483
HEK293T Normal Homo sapiens CVCL_0063
HCC827 Lung adenocarcinoma Homo sapiens CVCL_2063
BEAS-2B Normal Homo sapiens CVCL_0168
A-549 Lung adenocarcinoma Homo sapiens CVCL_0023
16HBE14o- Normal Homo sapiens CVCL_0112
In-vivo Model Established a xenograft model in BALB/c nude mice by inoculating HCC827-GR cells transfected with the constructs for circASK1 silencing, ASK1-272a.a overexpression and ASK1-272a.a overexpression/circASK1 knockdown
Experiment 2 Reporting the m6A-centered Drug Response by This Target Gene [6]
Response Summary Increased YTHDF2-mediated endoribonucleolytic cleavage of m6A-modified Circ_ASK1 accounts for its downregulation in gefitinib-resistant cells. Either METTL3 silencing or YTHDF2 silencing suppressed the decay of circASK1 in HCC827-GR cells. This study provides a novel therapeutic target to overcome gefitinib resistance in LUAD patients.
Responsed Disease Lung adenocarcinoma ICD-11: 2C25.0
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Cell Process Cell apoptosis
In-vitro Model SPC-A1 Endocervical adenocarcinoma Homo sapiens CVCL_6955
SK-LU-1 Lung adenocarcinoma Homo sapiens CVCL_0629
NCI-H1993 Lung adenocarcinoma Homo sapiens CVCL_1512
NCI-H1975 Lung adenocarcinoma Homo sapiens CVCL_1511
NCI-H1650 Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1483
HEK293T Normal Homo sapiens CVCL_0063
HCC827 Lung adenocarcinoma Homo sapiens CVCL_2063
BEAS-2B Normal Homo sapiens CVCL_0168
A-549 Lung adenocarcinoma Homo sapiens CVCL_0023
16HBE14o- Normal Homo sapiens CVCL_0112
In-vivo Model Established a xenograft model in BALB/c nude mice by inoculating HCC827-GR cells transfected with the constructs for circASK1 silencing, ASK1-272a.a overexpression and ASK1-272a.a overexpression/circASK1 knockdown
References
Ref 1 Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016 May;17(5):577-89. doi: 10.1016/S1470-2045(16)30033-X. Epub 2016 Apr 12.
Ref 2 Exosomal Delivery of FTO Confers Gefitinib Resistance to Recipient Cells through ABCC10 Regulation in an m6A-dependent Manner. Mol Cancer Res. 2021 Apr;19(4):726-738. doi: 10.1158/1541-7786.MCR-20-0541. Epub 2021 Feb 9.
Ref 3 The mechanism of m(6)A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by Beta-elemene. Cell Death Dis. 2020 Nov 11;11(11):969. doi: 10.1038/s41419-020-03148-8.
Ref 4 RNA methyltransferase METTL3 induces intrinsic resistance to gefitinib by combining with MET to regulate PI3K/AKT pathway in lung adenocarcinoma. J Cell Mol Med. 2021 Mar;25(5):2418-2425. doi: 10.1111/jcmm.16114. Epub 2021 Jan 24.
Ref 5 N(6)-methyladenosine (m(6)A) methyltransferase KIAA1429 accelerates the gefitinib resistance of non-small-cell lung cancer. Cell Death Discov. 2021 May 17;7(1):108. doi: 10.1038/s41420-021-00488-y.
Ref 6 A novel protein encoded by circASK1 ameliorates gefitinib resistance in lung adenocarcinoma by competitively activating ASK1-dependent apoptosis. Cancer Lett. 2021 Nov 1;520:321-331. doi: 10.1016/j.canlet.2021.08.007. Epub 2021 Aug 11.