Molecule Information

General Information of the Molecule (ID: Mol04253)

• Name: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) ,Homo sapiens
• Synonyms: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)
• Molecule Type: Protein

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) 3 drug(s) in total

Irinotecan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colon cancer [ICD-11: 2B90.1] [1]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Resistant Drug: Irinotecan
• Molecule Alteration: Function; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NF+kB signaling pathway; Activation; hsa04218
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW-480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: Immunoblotting assay; qRT-PCR; Immunofluorescence staining assay; Reporter Gene assay; RNA sequencing assay
• Experiment for Drug Resistance: Cell cytotoxicity assay; Tumorigenicity assay
• Mechanism Description: Our data suggest that irinotecan upregulates various oncogenes, proliferative pathways, and metastatic markers, which may compromise its efficacy. SN38 induces p53-independent CDKIs and regulates cancer cell growth. OPN silencing regulates the SN38-mediated increase in PD-L1. Inhibition of non-canonical NF-kappaB signaling by QNZ results in the regulation of SN38-induced survivin and ISG15 (Figure 7). The targeting of OPN, PD-L1, ISG15, and NF-kappaB pathways may elevate irinotecan potency and lead to its combination with immunomodulatory therapies for CRC prognostic strategies.

Stavudine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: cancer [ICD-11: 2D4Z] [2]

• Sensitive Disease: cancer [ICD-11: 2D4Z]
• Sensitive Drug: Stavudine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Interferon type I signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: FVB/N-TgN 202Mul mice model; Mus musculus
• Experiment for Molecule Alteration: Global transcriptome assay
• Experiment for Drug Resistance: L1 retrotransposition assay
• Mechanism Description: the acquisition of drug resistance by 4T1 cells was accompanied by an increase in the constitutive activity of interferon type I and NF-kappaB pathways and an elevated expression of LINE-1 elements, which are known to induce inflammatory responses via their products of reverse transcription. Treatment with NRTI reduced NF-kappaB activity and reverted drug resistance. Furthermore, the inducible expression of LINE-1 stimulated inflammatory response and increased the frequency of drug-resistant variants in a tumor cell population.

Venetoclax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic lymphocytic leukemia [ICD-11: 2A82.0] [3]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Function; Activation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: TNF signaling pathway; Activation; hsa04668
• Cell Pathway Regulation: Toll-like receptor signaling pathway; Activation; hsa04620
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• Cell Pathway Regulation: RANK-L/RANK signaling pathway; Regulation; N.A.
• In Vitro Model: HG-3 CLL cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: OSU-CLL cells; Blood; Homo sapiens (Human); CVCL_Y382
• Experiment for Molecule Alteration: Pathway enrichment analysis
• Experiment for Drug Resistance: RNA sequencing assay; ROS assay; Ferroptosis assay; Flow cytometry assay
• Mechanism Description: Venetoclax resistance can be driven by the upregulation of other anti-apoptotic BCL2 family members such as BCL-xL and MCL1 by NF-kappaB activation.

References

• Ref 1: Overcoming Irinotecan Resistance by Targeting Its Downstream Signaling Pathways in Colon Cancer. Cancers (Basel). 2024 Oct 15;16(20):3491.
• Ref 2: Inflammatory response to retrotransposons drives tumor drug resistance that can be prevented by reverse transcriptase inhibitors. Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2213146119.
• Ref 3: The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax. Hemato. 2024 Sep;5(3):321-339.