Disease Information

General Information of the Disease (ID: DIS00514)

• Name: Mature B-cell neoplasms/lymphoma
• ICD: ICD-11: 2A85

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Early growth response protein 1 (EGR1) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Mice, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: RNA seq
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The overexpression of EGR1 in ibrutinib-resistant cells is likely to result from the transcription factor TCF4-mediated EGR1 transcription and EGR1 self-regulation. Genetic and pharmacological inhibition of EGR1 restores the sensitivity of the resistant cells to ibrutinib, suggesting a role EGR1 plays in ibrutinib resistance. The underlying mechanism is that EGR1 mediates metabolic reprogramming to mitochondrial OXPHOS by transcriptional activation of PDP1, which increases ATP production.

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: We provide evidence that DNMT3A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: We provide evidence that DNMT4A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: We provide evidence that DNMT5A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: We provide evidence that DNMT6A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Mouse, with tumor cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: We provide evidence that DNMT7A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.

Venetoclax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCL cells; Blood; Homo sapiens (Human); CVCL_UU63
• In Vitro Model: UPF19U cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: UPF1H cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.

Preclinical Drug(s) 1 drug(s) in total

A-1155463

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [3]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Sensitive Drug: A-1155463
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCL cells; Blood; Homo sapiens (Human); CVCL_UU63
• In Vitro Model: UPF19U cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: UPF1H cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.

References

• Ref 1: EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma. Blood. 2023 Nov 30;142(22):1879-1894.
• Ref 2: Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma. Cell Rep Med. 2024 Apr 16;5(4):101484.
• Ref 3: Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies. Blood Adv. 2024 Oct 22;8(20):5279-5289.