Disease Information

General Information of the Disease (ID: DIS00544)

• Name: Diffuse large B-cell lymphoma
• ICD: ICD-11: 2A81

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: CDGSH iron-sulfur domain-containing protein 2 (CISD2) [2]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HBL-1/DOX cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Cell proliferation assay
• Mechanism Description: CISD2 may play a role in promoting tumor cell proliferation and drug resistance through ferroptosis and ferritinophagy. CISD2 expression levels were higher in HBL-1/DOX cells compared to HBL-1 cells.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: p52-RelB transcriptional regulator complex (p52-RelB) [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• In Vitro Model: OCI-LY19 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Doxorubicin-induced stress in resistant cells activates a distinct transcriptional signature that is enriched in metabolic reprogramming and oncogenic signalling. Selective and sustained activation of non-canonical NF-kappaB signalling in these resistant cells exacerbated their survival by augmenting glycolysis. In response to doxorubicin, p52-RelB complexes transcriptionally activated multiple glycolytic regulators with prognostic significance through increased recruitment at their gene promoters. Targeting p52-RelB and their targets in resistant cells increased doxorubicin sensitivity in vitro and in vivo.

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Tumor protein p53 (TP53) [4]

• Metabolic Type: Redox metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CD40L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: OCI-LY10 cells; Blood; Homo sapiens (Human); CVCL_8795
• In Vitro Model: OCI-LY18 cells; Blood; Homo sapiens (Human); CVCL_1880
• In Vitro Model: OCI-LY19 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vitro Model: OCI-LY3 cells; Blood; Homo sapiens (Human); CVCL_8800
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: U-2932 cells; Blood; Homo sapiens (Human); CVCL_1896
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition.

Key Molecule: BCL2 associated X protein (BAX) [4]

• Metabolic Type: Redox metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CD40L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: OCI-LY10 cells; Blood; Homo sapiens (Human); CVCL_8795
• In Vitro Model: OCI-LY18 cells; Blood; Homo sapiens (Human); CVCL_1880
• In Vitro Model: OCI-LY19 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vitro Model: OCI-LY3 cells; Blood; Homo sapiens (Human); CVCL_8800
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: U-2932 cells; Blood; Homo sapiens (Human); CVCL_1896
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition.

Key Molecule: Myeloid cell leukemia 1 (Mcl-1) [4]

• Metabolic Type: Redox metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CD40L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: OCI-LY10 cells; Blood; Homo sapiens (Human); CVCL_8795
• In Vitro Model: OCI-LY18 cells; Blood; Homo sapiens (Human); CVCL_1880
• In Vitro Model: OCI-LY19 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vitro Model: OCI-LY3 cells; Blood; Homo sapiens (Human); CVCL_8800
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: U-2932 cells; Blood; Homo sapiens (Human); CVCL_1896
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition.

Rituximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: B-lymphocyte antigen CD20 (CD20) [5]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Rituximab
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female B-NDG mice (5-7 weeks old) , with PDK4-overexpressing OCI-ly8 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression

Key Molecule: Pyruvate dehydrogenase kinase 4 (PDK4) [5]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Rituximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female B-NDG mice (5-7 weeks old) , with PDK4-overexpressing OCI-ly8 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Glutathione peroxidase 4 (GPX4) [6]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Rituximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SLC7A11/GSH/GPX4 signaling pathway; Regulation; N.A.
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• Experiment for Molecule Alteration: Western blot assay; GSH assay; MDA assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Rituximab exposure induced ferroptosis in OCI-LY1 cells. However, combination with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, indicating that ferroptosis plays a key role in rituximab-induced cell death. The SLC7A11/GSH/GPX4 signal transduction axis is the core pathway of ferroptosis, and SLC7A11 plays a major transport function in the cystine/glutamate anti-transporter (Xc-system). The extracellular cysteine is imported into the cell through the XC- system and then converted to cysteine to synthesize GSH. GPX4 uses reduced GSH as a cofactor to detoxify lipid peroxides into lipid alcohols, thereby preventing ferroptosis induced in cells.

Venetoclax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: B-cell lymphoma 2 (BCL2) [7]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Missense mutation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SU-DHL-2 cells; N.A.; Homo sapiens (Human); CVCL_9950
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL5 cells; Blood; Homo sapiens (Human); CVCL_1735
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL8 cells; Blood; Homo sapiens (Human); CVCL_2207
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL16 cells; Blood; Homo sapiens (Human); CVCL_1890
• In Vitro Model: Toledo cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• Experiment for Molecule Alteration: Western blot assay; RNA Sequencing assay; Flow cytometry
• Experiment for Drug Resistance: Cell survival and synergy assay; Caspase-3/7 apoptosis assay; Live/Dead assay
• Mechanism Description: Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: B-cell lymphoma 2 (BCL2) [8]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OCI-LY10 cells; Blood; Homo sapiens (Human); CVCL_8795
• In Vitro Model: OCI-LY3 cells; Blood; Homo sapiens (Human); CVCL_8800
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL16 cells; Blood; Homo sapiens (Human); CVCL_1890
• In Vitro Model: SUDHL2 cells; Blood; Homo sapiens (Human); CVCL_9550
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL5 cells; Blood; Homo sapiens (Human); CVCL_1735
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL8 cells; Blood; Homo sapiens (Human); CVCL_2207
• In Vitro Model: Toledo cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase-3/7 apoptosis assay
• Mechanism Description: We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [7]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Apoptosis signaling pathway; Inhibition; hsa04210
• In Vitro Model: SU-DHL-2 cells; N.A.; Homo sapiens (Human); CVCL_9950
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL5 cells; Blood; Homo sapiens (Human); CVCL_1735
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL8 cells; Blood; Homo sapiens (Human); CVCL_2207
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL16 cells; Blood; Homo sapiens (Human); CVCL_1890
• In Vitro Model: Toledo cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• Experiment for Molecule Alteration: Western blot assay; RNA Sequencing assay; Flow cytometry
• Experiment for Drug Resistance: Cell survival and synergy assay; Caspase-3/7 apoptosis assay; Live/Dead assay
• Mechanism Description: Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option.

Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) [7]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxidative phosphorylation; Activation; hsa00190
• Cell Pathway Regulation: Citrate cycle; Regulation; N.A.
• Cell Pathway Regulation: Glutathione metabolism; Activation; hsa00480
• Cell Pathway Regulation: Carbon metabolism; Activation; hsa01200
• In Vitro Model: SU-DHL-2 cells; N.A.; Homo sapiens (Human); CVCL_9950
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL5 cells; Blood; Homo sapiens (Human); CVCL_1735
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL8 cells; Blood; Homo sapiens (Human); CVCL_2207
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL16 cells; Blood; Homo sapiens (Human); CVCL_1890
• In Vitro Model: Toledo cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• Experiment for Molecule Alteration: Western blot assay; RNA Sequencing assay; Flow cytometry
• Experiment for Drug Resistance: Cell survival and synergy assay; Caspase-3/7 apoptosis assay; Live/Dead assay
• Mechanism Description: Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option.

Key Molecule: Bcl-x/Mcl-1 proteins [7]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Expression; F104L/V
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Apoptosis signaling pathway; Inhibition; hsa04210
• In Vitro Model: SU-DHL-2 cells; N.A.; Homo sapiens (Human); CVCL_9950
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL5 cells; Blood; Homo sapiens (Human); CVCL_1735
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL8 cells; Blood; Homo sapiens (Human); CVCL_2207
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL16 cells; Blood; Homo sapiens (Human); CVCL_1890
• In Vitro Model: Toledo cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• Experiment for Molecule Alteration: Western blot assay; RNA Sequencing assay; Flow cytometry
• Experiment for Drug Resistance: Cell survival and synergy assay; Caspase-3/7 apoptosis assay; Live/Dead assay
• Mechanism Description: Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option.

Key Molecule: Bcl-2 homologous antagonist/killer (BAK1) [7]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Apoptosis signaling pathway; Inhibition; hsa04210
• In Vitro Model: SU-DHL-2 cells; N.A.; Homo sapiens (Human); CVCL_9950
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL5 cells; Blood; Homo sapiens (Human); CVCL_1735
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL8 cells; Blood; Homo sapiens (Human); CVCL_2207
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL16 cells; Blood; Homo sapiens (Human); CVCL_1890
• In Vitro Model: Toledo cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• Experiment for Molecule Alteration: Western blot assay; RNA Sequencing assay; Flow cytometry
• Experiment for Drug Resistance: Cell survival and synergy assay; Caspase-3/7 apoptosis assay; Live/Dead assay
• Mechanism Description: Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option.

Patented Agent(s) 1 drug(s) in total

Erastin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: CDGSH iron-sulfur domain-containing protein 2 (CISD2) [2]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Sensitive Drug: Erastin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HBL-1/DOX cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: CCK8 assay; Cell proliferation assay
• Mechanism Description: A decrease in cell proliferation was observed in HBL-1/DOX cells transfected with shCISD2 and treated with 10 µM Erastin, compared to the inhibition of shCISD2 in HBL-1/DOX cells . Additionally, increases in iron , MDA , and ROS generation were induced by Erastin , while decreases in GSH and MMPs were also observed. Treatment of HBL-1/DOX cells with a combination of Erastin and shCISD2 resulted in a decrease in CISD2, p62, FTH1, and GPX4 levels, along with an increase in BECN1 and NCOA4. These findings suggest that inhibiting CISD2 can enhance the effects of Erastin by promoting increased ferroptosis and ferritinophagy, thereby contributing to the cell death of HBL-1/DOX cells.

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

Nirogacestat-Ipatasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurogenic locus notch homolog protein 2 (NOTCH2) [1]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Sensitive Drug: Nirogacestat-Ipatasertib
• Molecule Alteration: Missense mutation; Loss
• 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
• In Vitro Model: TMD8 cells; Lymphoid; Homo sapiens (Human); CVCL_A442
• In Vitro Model: HLY-1 cells; Lymph; Homo sapiens (Human); CVCL_H207
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• In Vitro Model: OCI-Ly7 cells; N.A.; Homo sapiens (Human); CVCL_1881
• In Vitro Model: 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]
• Sensitive Drug: Nirogacestat-Ipatasertib
• Molecule Alteration: Missense mutation; Loss
• 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
• In Vitro Model: TMD8 cells; Lymphoid; Homo sapiens (Human); CVCL_A442
• In Vitro Model: HLY-1 cells; Lymph; Homo sapiens (Human); CVCL_H207
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• In Vitro Model: OCI-Ly7 cells; N.A.; Homo sapiens (Human); CVCL_1881
• In Vitro Model: 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.

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

Rituximab/Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Naaladl2-as2 [9]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Sensitive Drug: Rituximab/Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: U-2932 cells; Blood; Homo sapiens (Human); CVCL_1896
• In Vitro Model: OCI-LY19 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vivo Model: Athymic BALB/c nude mice model; Mus musculus
• Experiment for Molecule Alteration: Fluorescence in situ hybridization assay; Small interfering RNA assay; Luciferase reporter assay; Fluorescent qPCR; Western blot assay
• Experiment for Drug Resistance: MTT assay; Drug sensitivity testing
• Mechanism Description: We observed elevated levels of NAALADL2-AS2 in DLBCL tissues. We discovered that NAALADL2-AS2 functions as ceRNA to inhibit expression of miR-34a, miR-125a, whereas overexpression of NAALADL2-AS2 indirectly upregulates expression of BCL-2. Interfering with NAALADL2-AS2 promoted apoptosis in DLBCL cells, resulting in approximately a 40% increase in sensitivity to doxorubicin and rituximab. In vivo experiments further confirmed that targeting NAALADL2-AS2 effectively suppressed tumor growth, leading to upregulation of miR-34a and miR-125a, downregulation of BCL-2, and enhanced apoptosis in DLBCL cells, which significantly improved their sensitivity to doxorubicin and rituximab by approximately 50%.

References

• Ref 1: DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance. Blood. 2023 Sep 14;142(11):973-988.
• Ref 2: Inhibition of CISD2 enhances sensitivity to doxorubicin in diffuse large B-cell lymphoma by regulating ferroptosis and ferritinophagy. Front Pharmacol. 2024 Nov 13;15:1482354.
• Ref 3: Sustained activation of non-canonical NF-kappaB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL. Leukemia. 2023 Feb;37(2):441-452.
• Ref 4: Pharmacologic Targeting of Mcl-1 Induces Mitochondrial Dysfunction and Apoptosis in B-Cell Lymphoma Cells in a TP53- and BAX-Dependent Manner. Clin Cancer Res. 2021 Sep 1;27(17):4910-4922.
• Ref 5: Pyruvate dehydrogenase kinase 4-mediated metabolic reprogramming is involved in rituximab resistance in diffuse large B-cell lymphoma by affecting the expression of MS4A1/CD20. Cancer Sci. 2021 Sep;112(9):3585-3597.
• Ref 6: Rituximab induces ferroptosis and RSL3 overcomes rituximab resistance in diffuse large B-cell lymphoma cells. Arch Biochem Biophys. 2024 Nov;761:110188.
• Ref 7: Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma. Cancers (Basel). 2024 Jun 3;16(11):2130.
• Ref 8: Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma. Cancers (Basel). 2024 Jun 3;16(11):2130.
• Ref 9: NAALADL2-AS2 functions as a competing endogenous RNA to regulate apoptosis and drug resistance in DLBCL. Cancer Biol Ther. 2024 Dec 31;25(1):2432690.