Drug Information

Drug (ID: DG02155) and It's Reported Resistant Information

• Name: BTK inhibitors
• Synonyms: BTK inhibitors
• Indication:
  In total 1 Indication(s)
  . .; .; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [1]

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor tyrosine-protein kinase erbB-4 (ERBB4) [1]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

Key Molecule: Proheparin-binding EGF-like growth factor (HBEGF) [1]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

Key Molecule: Pro-neuregulin-2, membrane-bound isoform (NRG2) [1]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

References

• Ref 1: ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms. Mol Cancer Ther. 2024 Mar 4;23(3):368-380.