Drug Information

Drug (ID: DG01214) and It's Reported Resistant Information

• Name: Dacomitinib
• Synonyms: Dacomitinib; 1110813-31-4; PF299804; Dacomitinib (PF299804, PF299); PF-00299804; UNII-2XJX250C20; (2E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide; (E)-N-(4-((3-chloro-4-fluorophenyl)aMino)-7-Methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enaMide; 2XJX250C20; PF 00299804-03; Vizimpro; PF-299804; PF-00299804-03; (E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide; C24H25ClFN5O2; (2e)-N-{4-[(3-Chloro-4-Fluorophenyl)amino]-7-Methoxyquinazolin-6-Yl}-4-(Piperidin-1-Yl)but-2-Enamide; Dacomitinib [USAN:INN]; dacomitinibum; PF299; (E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-4-(piperidin-1-yl)but-2-enamide; Dacomitinib (INN); Dacomitinib anhydrous; Dacomitinib (PF299804); MLS006011275; GTPL7422; CHEMBL2110732; PF-00299804 dacomitinib; CHEBI:91466; DTXSID50149493; EX-A030; QCR-174; CHEBI:132268; BDBM112499; Dacomitinib (PF-00299804); AMY21292; AOB87383; AOB87735; BCP02530; MFCD19443734; NSC765888; NSC800084; PF-299; s2727; ZINC72266312; AKOS025401818; CCG-264987; CS-0500; DB11963; NSC-765888; NSC-800084; US8623883, No. 2; NCGC00263185-09; NCGC00263185-10; AC-25915; AS-57686; HY-13272; SMR004703025; PF299804; ; ; PF299; D5450; SW219155-1; Y0338; D09883; Dacomitinib (PF299804, PF-00299804); PF-299804 (Dacomitinib PF-00299804); J-500784; Q17130597; (2E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-(piperidin-1-yl)but-2-enamide; (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide; 2-Butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-6-quinazolinyl)-4-(1-piperidinyl)-, (2E)-
• Indication:
  In total 3 Indication(s)
  Non-small-cell lung cancer [ICD-11: 2C25]; Approved; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Approved; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Lung cancer [ICD-11: 2C25]; [2]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [4]
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [3]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• Target: Erbb2 tyrosine kinase receptor (HER2); ERBB2_HUMAN; [1]
• Target: Erbb4 tyrosine kinase receptor (Erbb-4); ERBB4_HUMAN; [1]
• Formula: C24H25ClFN5O2
• IsoSMILES: COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)NC(=O)/C=C/CN4CCCCC4
• InChI: 1S/C24H25ClFN5O2/c1-33-22-14-20-17(24(28-15-27-20)29-16-7-8-19(26)18(25)12-16)13-21(22)30-23(32)6-5-11-31-9-3-2-4-10-31/h5-8,12-15H,2-4,9-11H2,1H3,(H,30,32)(H,27,28,29)/b6-5+
• InChIKey: LVXJQMNHJWSHET-AATRIKPKSA-N
• PubChem CID: 11511120
• ChEBI ID: CHEBI:91466
• TTD Drug ID: D06XXH
• VARIDT ID: DR00109
• INTEDE ID: DR0407
• DrugBank ID: DB11963

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: IF-insertion; p.Y764_V765insHH (c.2292_2293insCATCAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Epidermal growth factor receptor (EGFR) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Epidermal growth factor receptor (EGFR) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [4]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Duplication; p.Y772_A775 (c.2314_2325)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Complex-indel; p.D770_770delinsGY (c.2308_2310delinsGGTTAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Epidermal growth factor receptor (EGFR) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.E709K (c.2125G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: myelomonocyti cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: macrophage-like cells; N.A.; N.A.; N.A.
• In Vitro Model: IL3-dependent murine pro-B cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Balb/C mouse leukemia cells; Blood; Mus musculus (Mouse); CVCL_9099
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Epidermal growth factor receptor (EGFR) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Complex-indel; p.E709_T710delinsD (c.2127_2129delAAC)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: myelomonocyti cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: macrophage-like cells; N.A.; N.A.; N.A.
• In Vitro Model: IL3-dependent murine pro-B cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Balb/C mouse leukemia cells; Blood; Mus musculus (Mouse); CVCL_9099
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Epidermal growth factor receptor (EGFR) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.G719A (c.2156G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: myelomonocyti cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: macrophage-like cells; N.A.; N.A.; N.A.
• In Vitro Model: IL3-dependent murine pro-B cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Balb/C mouse leukemia cells; Blood; Mus musculus (Mouse); CVCL_9099
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Complex-indel; p.M774_774delinsWLV (c.2320_2322delinsTGGCTTGTA)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Duplication; p.G778_P780 (c.2332_2340)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: IF-insertion; p.G778_S779insCPG (c.2335_2336insGTCCTGGTT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Complex-indel; p.G776_776delinsVC (c.2326_2328delinsGTATGT)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Duplication; p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB) [2]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ca2+/calcineurin/MEK/ERK1/2 signaling pathway; Regulation; N.A.
• In Vitro Model: PC9/DR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/GR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/OR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTS assay; Flow cytometric assay; Colony formation assay
• Mechanism Description: Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [6]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.64 Å; PDB: 4LI5
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.47 Å; PDB: 2ITV

RMSD: 1.34; TM score: 0.90001; Amino acid change: L858R

• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Epidermal growth factor receptor (EGFR) [3]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Duplication; p.N771_H773 (c.2311_2319)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Epidermal growth factor receptor (EGFR) [7]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G719S (c.2155G>A)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Epidermal growth factor receptor (EGFR) [7]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G719C (c.2155G>T)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Epidermal growth factor receptor (EGFR) [7]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G719A (c.2156G>C)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Epidermal growth factor receptor (EGFR) [3]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: IF-insertion; p.P772_H773insPNP (c.2317_2318insCTAACCCTC)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Key Molecule: Epidermal growth factor receptor (EGFR) [8]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: IF-deletion; p.G729_D761 (c.2185_2283)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lung; N.A.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [9]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Complex-indel; p.M774_774delinsWLV (c.2320_2322delinsTGGCTTGTA)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lung; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Clinical measurement assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [9]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Duplication; p.G778_P780 (c.2332_2340)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lung; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Clinical measurement assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [9]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: IF-insertion; p.P780_Y781 (c.2340_2341)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lung; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Clinical measurement assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [9]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Complex-indel; p.M774delinsWLV (c.2320delinsTGGCTGG)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lung; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Clinical measurement assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [9]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Duplication; p.P780_Y781 (c.2340_2341)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lung; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Clinical measurement assay

Ovarian cancer [ICD-11: 2C73]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Signal transducer activator transcription 3 (STAT3) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: LDH assay; Flow cytometry assay
• Mechanism Description: Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity.

Key Molecule: Mitogen-activated protein kinase (MAPK) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: LDH assay; Flow cytometry assay
• Mechanism Description: Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity.

Key Molecule: AKT serine/threonine kinase (AKT) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: LDH assay; Flow cytometry assay
• Mechanism Description: Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity.

Key Molecule: Epidermal growth factor receptor (EGFR) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: LDH assay; Flow cytometry assay
• Mechanism Description: Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity.

Key Molecule: Human epidermal growth factor receptor 2 (HER2) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: LDH assay; Flow cytometry assay
• Mechanism Description: Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity.

Key Molecule: Mitogen-activated protein kinase 12 (MAPK12) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: LDH assay; Flow cytometry assay
• Mechanism Description: Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity.

References

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