Drug Information

Drug (ID: DG01864) and It's Reported Resistant Information
Name
PI3K pathway inhibitors
Synonyms
PI3K pathway inhibitors
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Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[1]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[2]
Type(s) of Resistant Mechanism of This Drug
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Breast cancer [ICD-11: 2C60]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: PI3-kinase alpha (PIK3CA) [1]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Copy number gain
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model KPL-4 cells Breast Homo sapiens (Human) CVCL_5310
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter Glo luminescence assay; PathScan RTK signaling antibody array assay
Key Molecule: PI3-kinase beta (PIK3CB) [2]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.D1067Y (c.3199G>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
SUM-52PE cells Pleural effusion Homo sapiens (Human) CVCL_3425
Rat2 cells Whole embryo Rattus norvegicus (Rat) CVCL_0513
HCC-1569 cells Breast Homo sapiens (Human) CVCL_1255
EVSA-T cells Ascites Homo sapiens (Human) CVCL_1207
A-498 cells Kidney Homo sapiens (Human) CVCL_1056
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: phosphoinositide-3-dependent protein kinase 1 (PDPK1) [3]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Copy number gain
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Breast N.A.
In Vivo Model SCID/NCr (BALB/c background) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The copy number gain in gene PDPK1 cause the sensitivity of PI3K pathway inhibitors by unusual activation of pro-survival pathway.
Head and neck cancer [ICD-11: 2D42]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [4]
Sensitive Disease Head and neck cancer [ICD-11: 2D42.0]
 Disease Info 
Molecule Alteration Missense mutation
p.E17K (c.49G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 1UNP
Mutant Type Structure Method: X-ray diffraction Resolution: 1.94  Å
PDB: 2UZR
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.26
TM score: 0.99569
Amino acid change:
E17K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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90
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110
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120
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Mechanism Description The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of PI3K pathway inhibitors by aberration of the drug's therapeutic target
References
Ref 1 Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancerOncogenesis. 2013 Dec 23;2(12):e83. doi: 10.1038/oncsis.2013.46.
Ref 2 Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110BetaCancer Res. 2016 Mar 1;76(5):1193-203. doi: 10.1158/0008-5472.CAN-15-2201. Epub 2016 Jan 12.
Ref 3 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinomaCancer Res. 2009 Aug 1;69(15):6299-306. doi: 10.1158/0008-5472.CAN-09-0820. Epub 2009 Jul 14.
Ref 4 Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell CarcinomaClin Cancer Res. 2016 Jun 15;22(12):2939-49. doi: 10.1158/1078-0432.CCR-15-2314. Epub 2016 Jan 13.

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