Disease Information

General Information of the Disease (ID: DIS00049)

• Name: Lymphoma
• ICD: ICD-11: 2A90- 2A85

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytidine deaminase (CDA) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Also opposing the activation pathway are the two deaminase CDA and deoxycytidine monophosphate deaminase (dCMPD). Cytidine deaminase is a multi-subunit enzyme involved in the maintenance of the pyrimidine nucleotide pool within the cell and physiologically catalyzes the hydrolytic deamination of cytidine to uridine and deoxycytidine to deoxyuridine. In cytarabine biotransformation, CDA removes the amine group from its cytosine and converts the drug into the inactive uracil arabinoside derivative.

Key Molecule: Cardiolipin synthase (CLS) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CMPD deaminates cytarabine-monophosphate to arabinosyl-uracil-monophosphate. A crucial role for this latter enzyme has been suggested in the metabolism of cytarabine-monophosphate in T-lymphoblastic leukemia.

Key Molecule: Deoxycytidine kinase (DCK) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Deoxycitidine kinase plays a pivotal role since phosphorylation of cytarabine preserves intracellular retention of the drug and prevents from inactivation to its uridine derivative, uracil arabinoside, by cytidine deaminase. The intracellular accumulation of cytarabine triphosphate, the active cytotoxic metabolite, is proportional to the cellular DCk level which has led to the conclusion that DCk enzyme retains a rate-limiting role for the activation of cytarabine.

Key Molecule: UMP-CMP kinase (CMPK1) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Activation of cytarabine occurs by means of the step wise de novo synthesis of 5'-mono-, di-, and triphosphate derivatives throughout the sequential action of deoxycytidine kinase (DCk), deoxycytidine monophosphate kinase (dCMk), and nucleoside diphosphate kinase (NDk) encoded by the NME1 gene. Phosphorylated cytarabine metabolites interfere with the cellular pool of natural nucleosides, are incorporated into DNA and inhibit DNA synthesis in a competitive fashion. In vitro studies have revealed that the intracellular concentrations of cytarabine-triphosphate are higher in cytarabine sensitive cells than in resistant cells.

Key Molecule: Nucleoside diphosphate kinase A (NME1) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Activation of cytarabine occurs by means of the step wise de novo synthesis of 5'-mono-, di-, and triphosphate derivatives throughout the sequential action of deoxycytidine kinase (DCk), deoxycytidine monophosphate kinase (dCMk), and nucleoside diphosphate kinase (NDk) encoded by the NME1 gene. Phosphorylated cytarabine metabolites interfere with the cellular pool of natural nucleosides, are incorporated into DNA and inhibit DNA synthesis in a competitive fashion. In vitro studies have revealed that the intracellular concentrations of cytarabine-triphosphate are higher in cytarabine sensitive cells than in resistant cells.

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Since monophosphorilated intermediate of cytarabine activation is reduced by cytosolic 5'-nucleotidases NT5C2 and NT5C3, the activity level of this enzyme may represent one of the factors affecting the clinical outcome of cytarabine therapy. Increased expression of NT5C2 has been correlated with resistance to cytarabine chemotherapy and to a lower survival rate in a hundred patients undergoing cytarabine chemotherapy. An increase in the NT5C2 has emerged as a mechanism of resistance to cytarabine. Patients with AML and low expression level of NT5C2 have a better overall survival after treatment with cytarabine than patients with high expression. NT5C2 is implicated in pharmacokinetic of cytarabine has been associated with poor clinical outcome.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C10 (ABCC10) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Uptake and accumulation of cytarabine is also regulated by transmembrane transporter proteins of the ABC family, also called human multidrug resistance-associated protein (MRP) family, namely ABCC10 (MRP7) and ABCC11 (MRP8) specifically committed to efflux of deoxynucleotides inactive metabolites and to temper intracellular pools of phosphorylated deoxynucleotides. The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.

Key Molecule: ATP-binding cassette sub-family C11(ABCC11) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Uptake and accumulation of cytarabine is also regulated by transmembrane transporter proteins of the ABC family, also called human multidrug resistance-associated protein (MRP) family, namely ABCC10 (MRP7) and ABCC11 (MRP8) specifically committed to efflux of deoxynucleotides inactive metabolites and to temper intracellular pools of phosphorylated deoxynucleotides. The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.

Key Molecule: Solute carrier family 29 member 1 (SLC29A1) [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Cytarabine gains entry into cells primarily as a false substrate through specialized nucleoside transporter proteins of SLC family, the human equilibrative nucleoside transportershENT1 and hENT2 (encoded by the gene SLC29A1 and SCL29A2, respectively) and the human concentrative nucleoside transporters hCNT3 (encoded by the gene SLC28A3). The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.

Tazemetostat

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [2]

• Sensitive Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Missense mutation; p.Y646F (c.1937A>T)
• Sensitive Drug: Tazemetostat
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: CRL-2959 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_2206
• In Vitro Model: CRL-2632 cells; Pleural effusion; Homo sapiens (Human); CVCL_3326
• In Vitro Model: CRL-2631 cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• In Vitro Model: CRL-2630 cells; Lymph node; Homo sapiens (Human); CVCL_3302
• In Vitro Model: CRL-2261 cells; Ascites; Homo sapiens (Human); CVCL_1660
• In Vitro Model: ACC-576 cells; Pleural effusion; Homo sapiens (Human); CVCL_1889
• In Vitro Model: ACC-575 cells; Pleural effusion; Homo sapiens (Human); CVCL_1902
• In Vitro Model: ACC-528 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vitro Model: ACC-32 cells; Pleural effusion; Homo sapiens (Human); CVCL_1325
• In Vivo Model: Sprague-Dawley rat model; Rattus norvegicus
• Experiment for Molecule Alteration: ChIP-PCR
• Experiment for Drug Resistance: Cell Titer Glo assay; Tumor volume measurement assay; Immunohistochemistry assay

Venetoclax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [3]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Missense mutation; p.F104I (c.310T>A)
• Resistant Drug: Venetoclax
• Experimental Note: Identified from the Human Clinical Data

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

EZH2 inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [2]

• Sensitive Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Missense mutation; p.Y641F (c.1922A>T)
• Sensitive Drug: EZH2 inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: CRL-2959 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_2206
• In Vitro Model: CRL-2632 cells; Pleural effusion; Homo sapiens (Human); CVCL_3326
• In Vitro Model: CRL-2631 cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• In Vitro Model: CRL-2630 cells; Lymph node; Homo sapiens (Human); CVCL_3302
• In Vitro Model: CRL-2261 cells; Ascites; Homo sapiens (Human); CVCL_1660
• In Vitro Model: ACC-576 cells; Pleural effusion; Homo sapiens (Human); CVCL_1889
• In Vitro Model: ACC-575 cells; Pleural effusion; Homo sapiens (Human); CVCL_1902
• In Vitro Model: ACC-528 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vitro Model: ACC-32 cells; Pleural effusion; Homo sapiens (Human); CVCL_1325
• In Vivo Model: Sprague-Dawley rat model; Rattus norvegicus
• Experiment for Molecule Alteration: ChIP-PCR
• Experiment for Drug Resistance: Cell Titer Glo assay; Tumor volume measurement assay; Immunohistochemistry assay

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [4]

• Sensitive Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Missense mutation; p.A677G (c.2030C>G)
• Sensitive Drug: EZH2 inhibitors
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293 cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Determination of inhibitor IC50 values in the PMT panel assay
• Mechanism Description: The missense mutation p.A677G (c.2030C>G) in gene EZH2 cause the sensitivity of EZH2 inhibitors by aberration of the drug's therapeutic target

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

EPZ005687

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [4]

• Sensitive Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Missense mutation; p.Y641F (c.1922A>T)
• Sensitive Drug: EPZ005687
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293 cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Determination of inhibitor IC50 values in the PMT panel assay
• Mechanism Description: The missense mutation p.Y641F (c.1922A>T) in gene EZH2 cause the sensitivity of EPZ005687 by aberration of the drug's therapeutic target

Pyridone 6

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Sensitive Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Missense mutation; p.A572V (c.1715C>T)
• Sensitive Drug: Pyridone 6
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NK-S1 cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.A572V (c.1715C>T) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Sensitive Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Molecule Alteration: Missense mutation; p.A573V (c.1718C>T)
• Sensitive Drug: Pyridone 6
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NK-S1 cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.A573V (c.1718C>T) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

References

• Ref 1: Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers. Cancers (Basel). 2021 Feb 25;13(5):966. doi: 10.3390/cancers13050966.
• Ref 2: Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphomaMol Cancer Ther. 2014 Apr;13(4):842-54. doi: 10.1158/1535-7163.MCT-13-0773. Epub 2014 Feb 21.
• Ref 3: Characterization of a novel venetoclax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphomaBr J Haematol. 2019 Sep;186(6):e188-e191. doi: 10.1111/bjh.16069. Epub 2019 Jun 24.
• Ref 4: A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cellsNat Chem Biol. 2012 Nov;8(11):890-6. doi: 10.1038/nchembio.1084. Epub 2012 Sep 30.
• Ref 5: Janus kinase 3-activating mutations identified in natural killer/T-cell lymphomaCancer Discov. 2012 Jul;2(7):591-7. doi: 10.1158/2159-8290.CD-12-0028. Epub 2012 Jun 15.