Drug Information

Drug (ID: DG02160) and It's Reported Resistant Information
Name
Nirogacestat-Ipatasertib
Synonyms
Nirogacestat-Ipatasertib
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Indication
In total 1 Indication(s)
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[1]
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
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Diffuse large B-cell lymphoma [ICD-11: 2A81]
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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: Neurogenic locus notch homolog protein 2 (NOTCH2) [1]
Sensitive Disease Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
 Disease Info 
Molecule Alteration Missense mutation
Loss
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Notch signaling pathway Inhibition hsa04330
In Vitro Model U-2932 cells Blood Homo sapiens (Human) CVCL_1896
TMD8 cells Lymphoid Homo sapiens (Human) CVCL_A442
HLY-1 cells Lymph Homo sapiens (Human) CVCL_H207
SUDHL6 cells Blood Homo sapiens (Human) CVCL_2206
SUDHL10 cells Blood Homo sapiens (Human) CVCL_1889
OCI-Ly1 cells Bone marrow Homo sapiens (Human) CVCL_1879
OCI-Ly7 cells N.A. Homo sapiens (Human) CVCL_1881
Val cells Bone marrow Homo sapiens (Human) CVCL_1819
In Vivo Model NSG mice model Mus musculus
Experiment for
Molecule Alteration		 Immunoprecipitation assay; Biotin AP assay; Immunoblotting assay
Experiment for
Drug Resistance		 CRISPR screen assay; MS assay; Flow cytometry assay; Drug sensitivity assay; RNA sequencing assay; Chromatin immunoprecipitation followed by sequencing assay
Mechanism Description DLBCL-associated NOTCH2 mutations evade ubiquitin-dependent degradation via the E3 ligases KLHL6 and FBXW7 and promote chemoresistance.Inhibition of gamma-secretase and AKT with nirogacestat and ipatasertib synergistically promotes CHOP-resistant DLBCL destruction.
Key Molecule: Kelch-like protein 6 (KLHL6) [1]
Sensitive Disease Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
 Disease Info 
Molecule Alteration Missense mutation
Loss
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Notch signaling pathway Inhibition hsa04330
In Vitro Model U-2932 cells Blood Homo sapiens (Human) CVCL_1896
TMD8 cells Lymphoid Homo sapiens (Human) CVCL_A442
HLY-1 cells Lymph Homo sapiens (Human) CVCL_H207
SUDHL6 cells Blood Homo sapiens (Human) CVCL_2206
SUDHL10 cells Blood Homo sapiens (Human) CVCL_1889
OCI-Ly1 cells Bone marrow Homo sapiens (Human) CVCL_1879
OCI-Ly7 cells N.A. Homo sapiens (Human) CVCL_1881
Val cells Bone marrow Homo sapiens (Human) CVCL_1819
In Vivo Model NSG mice model Mus musculus
Experiment for
Molecule Alteration		 Immunoprecipitation assay; Biotin AP assay; Immunoblotting assay
Experiment for
Drug Resistance		 CRISPR screen assay; MS assay; Flow cytometry assay; Drug sensitivity assay; RNA sequencing assay; Chromatin immunoprecipitation followed by sequencing assay
Mechanism Description DLBCL-associated NOTCH2 mutations evade ubiquitin-dependent degradation via the E3 ligases KLHL6 and FBXW7 and promote chemoresistance.Inhibition of gamma-secretase and AKT with nirogacestat and ipatasertib synergistically promotes CHOP-resistant DLBCL destruction.
References
Ref 1 DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance. Blood. 2023 Sep 14;142(11):973-988.

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