Molecule Information

General Information of the Molecule (ID: Mol01161)
Name
Phosphatidylinositol 3-kinase (PI3K) ,Homo sapiens
Molecule Type
Protein
Gene Name
PI3K
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
2 drug(s) in total
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Eribulin
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [1]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Eribulin
 Drug Info 
Molecule Alteration Function
Activation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Breast cancer cells Breast Homo sapiens (Human) N.A.
In Vivo Model Patient-derived tumour xenograft model Mus musculus
Experiment for
Molecule Alteration		 Targeted exome sequencing assay; Western blot analysis
Experiment for
Drug Resistance		 Crystal violet cell proliferation assay
Mechanism Description PI3K activation promotes resistance to eribulin in HER2-negative breast cancer.
Fluorouracil
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [2]
Resistant Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Resistant Drug Fluorouracil
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT/mTOR signaling pathway Inhibition hsa04151
In Vitro Model MKN-45/R cells Gastric Homo sapiens (Human) N.A.
MKN-74/R cells Gastric Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay; qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells.
Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [2]
Resistant Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Resistant Drug Fluorouracil
 Drug Info 
Molecule Alteration Phosphorylation
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT/mTOR signaling pathway Inhibition hsa04151
In Vitro Model MKN-45/R cells Gastric Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay; qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells.
Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [2]
Resistant Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Resistant Drug Fluorouracil
 Drug Info 
Molecule Alteration Phosphorylation
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT/mTOR signaling pathway Inhibition hsa04151
In Vitro Model MKN-74/R cells Gastric Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay; qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells.
Investigative Drug(s)
1 drug(s) in total
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Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2] [3]
Resistant Disease B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
 Disease Info 
Resistant Drug Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Phosphatidylinositol 3-kinase gamma Regulation N.A.
In Vitro Model TS cells Head and Neck Homo sapiens (Human) CVCL_VH06
SU-DHL-1 cells Pleural effusion Homo sapiens (Human) CVCL_0538
SUP-M2 cells Colon Homo sapiens (Human) CVCL_2209
JB6 [Human anaplastic large cell lymphoma] cells Lymphoid Homo sapiens (Human) CVCL_H633
KARPAS-299 cells Peripheral blood Homo sapiens (Human) CVCL_1324
DEL cells Pleural effusion Homo sapiens (Human) CVCL_1170
L-82 cells Pleural effusion Homo sapiens (Human) CVCL_2098
Mac-1 cells Lymph Homo sapiens (Human) CVCL_H631
FE-PD cells Lymph Homo sapiens (Human) CVCL_H614
CEM cells Lymph Homo sapiens (Human) N.A.
Jurkat cells Pleural effusion Homo sapiens (Human) CVCL_0065
Murine cells Lymph Homo sapiens (Human) N.A.
In Vivo Model CD4-NPM-ALK xenograft mice model; PI3KgammaCX/CX xenograft mice model; PI3Kgamma-/- xenograft mice model Mus musculus
Experiment for
Molecule Alteration		 Western blot assay; Fluorescence in situ hybridization assay; Histology assay; Immunohistochemistry; qRT-PCR; Flow cytometry
Experiment for
Drug Resistance		 Cell proliferation assay; Apoptosis assay; Cell viability assay; Drug sensitivity assay; Chemokine assay
Mechanism Description Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase gamma (PI3K-gamma) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kgamma expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kgamma, and PI3Kdelta were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kgamma isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kgamma/delta inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kgamma or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.
References
Ref 1 PI3K activation promotes resistance to eribulin in HER2-negative breast cancer .Br J Cancer. 2021 Apr;124(9):1581-1591. doi: 10.1038/s41416-021-01293-1. Epub 2021 Mar 15. 10.1038/s41416-021-01293-1
Ref 2 Inhibition of PI3K/Akt/mTOR Signaling Pathway Suppresses 5-Fluorouracil Resistance in Gastric Cancer. Mol Biotechnol. 2024 Dec;66(12):3640-3654.
Ref 3 Targeting CCR7-PI3Kgamma overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma. Sci Transl Med. 2023 Jun 28;15(702):eabo3826.

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