Drug Information

Drug (ID: DG01268) and It's Reported Resistant Information

• Name: Venetoclax
• Synonyms: Venetoclax; 1257044-40-8; ABT-199; Venclexta; GDC-0199; ABT199; ABT 199; Venetoclax (ABT199); UNII-N54AIC43PW; GDC 0199; RG7601; Venetoclax; Abt-199; 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; Venetoclax (ABT-199); RG-7601; N54AIC43PW; ABT-199 (GDC-0199); 2-(1H-Pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methy; 4-[4-[[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzamide; venclyxto; BDBM189459; 4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide; 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(oxan-4-ylmethyl)amino]benzene}sulfonyl)-2-{1H-pyrrolo[2,3-b]pyridin-5-yloxy}benzamide; 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-n-({3-nitro-4-[(tetrahydro-2h-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1h-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-{4-[(4'-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1'-biphenyl]]-2-yl)methyl]piperazin-1-yl}-N-(3-nitro-4-{[(oxan-4-yl)methyl]amino}benzene-1-sulfonyl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide; benzamide, 4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl)methyl)-1-piperazinyl)-n-((3-nitro-4-(((tetrahydro-2h-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(1h-pyrrolo(2,3-b)pyridin-5-yloxy)-; Venetoclax [USAN:INN]; Venclexta (TN); Benzamide, 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-; Venetoclax(ABT-199); C45H50ClN7O7S; MLS006010298; SCHEMBL523816; Venetoclax (JAN/USAN/INN); AMY343; GTPL8318; CHEMBL3137309; SCHEMBL19236295; BDBM60828; AOB5080; DTXSID30154863; EX-A168; CHEBI:133021; HMS3653J06; HMS3745E07; BCP06811; BDBM50162774; MFCD23160052; NSC766270; AKOS025289539; ZINC150338755; CCG-270543; CS-1155; DB11581; KS-1470; NSC-766270; SB16499; NCGC00345789-01; NCGC00345789-05; NCGC00345789-10; NCGC00345789-11; AC-28754; DA-35360; HY-15531; QC-11704; SMR004701366; FT-0699586; S8048; SW219672-1; X3609; J3.516.625D; D10679; US9174982, 5; A850921; US9174982, 369; J-005269; Q23671272; 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 4-[4-[[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-{4-[(4'-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1'-biphenyl]]-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(oxan-4-yl; ABT-199; ; ; GDC 0199; ; ; 4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
• Indication:
  In total 3 Indication(s)
  Chronic lymphocytic leukaemia [ICD-11: 2A82]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Chronic lymphocytic leukemia [ICD-11: 2A82]; [1]
  Lymphoma [ICD-11: 2A90- 2A85]; [2]
  Mature T-cell lymphoma [ICD-11: 2A90]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
  Chronic lymphocytic leukemia [ICD-11: 2A82]; [4]
  Diffuse large B-cell lymphoma [ICD-11: 2A81]; [5]
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [6]
• Target: Apoptosis regulator Bcl-2 (BCL-2); BCL2_HUMAN; [1]
• Formula: C45H50ClN7O7S
• IsoSMILES: CC1(CCC(=C(C1)C2=CC=C(C=C2)Cl)CN3CCN(CC3)C4=CC(=C(C=C4)C(=O)NS(=O)(=O)C5=CC(=C(C=C5)NCC6CCOCC6)[N+](=O)[O-])OC7=CN=C8C(=C7)C=CN8)C
• InChI: 1S/C45H50ClN7O7S/c1-45(2)15-11-33(39(26-45)31-3-5-34(46)6-4-31)29-51-17-19-52(20-18-51)35-7-9-38(42(24-35)60-36-23-32-12-16-47-43(32)49-28-36)44(54)50-61(57,58)37-8-10-40(41(25-37)53(55)56)48-27-30-13-21-59-22-14-30/h3-10,12,16,23-25,28,30,48H,11,13-15,17-22,26-27,29H2,1-2H3,(H,47,49)(H,50,54)
• InChIKey: LQBVNQSMGBZMKD-UHFFFAOYSA-N
• PubChem CID: 49846579
• ChEBI ID: CHEBI:133021
• TTD Drug ID: D00PBX
• VARIDT ID: DR00008
• DrugBank ID: DB11581

Type(s) of Resistant Mechanism of This Drug

  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 Their Corresponding Diseases

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

Diffuse large B-cell lymphoma [ICD-11: 2A81]

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]
• 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) [5]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• 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]
• 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]
• 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]
• 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]
• 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.

Chronic lymphocytic leukemia [ICD-11: 2A82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [8]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.G101V (c.302G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KMS-12-PE cells; Pleural effusion; Homo sapiens (Human); CVCL_1333
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Bcl-2-binding component 3 (BBC3) [4]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: B-cell lymphoma cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) [9]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• 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.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• 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.

Mature T-cell lymphoma [ICD-11: 2A90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: CAMPATH-1 antigen (CD52) [3]

• Resistant Disease: t-cell prolymphocytic leukemia [ICD-11: 2A90.0]
• Molecule Alteration: Expressiom; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: T-cell prolymphocytic leukemia patient; Homo sapiens
• Experiment for Molecule Alteration: Flow cytometry
• Experiment for Drug Resistance: Overall survival assay
• Mechanism Description: MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed.

Lymphoma [ICD-11: 2A90- 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

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

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [10]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1048 shp53 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H211 shp53 cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: Fluorescence-activated cell sorting assay; Cell viability assay
• Mechanism Description: Down-Regulation of Onc-p53 Increases BIM Expression and Sensitizes to Venetoclax in SCLC-P Cells. Down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells

Key Molecule: Cellular tumor antigen p53 (TP53) [10]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1048 shp53 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H211 shp53 cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Fluorescence-activated cell sorting assay; Cell viability assay
• Mechanism Description: Down-Regulation of Onc-p53 Increases BIM Expression and Sensitizes to Venetoclax in SCLC-P Cells. Down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells

References

• Ref 1: How I treat chronic lymphocytic leukemia after venetoclax .Blood. 2021 Aug 5;138(5):361-369. doi: 10.1182/blood.2020008502. 10.1182/blood.2020008502
• Ref 2: 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 3: Methotrexate, Hydrocortisone, Vincristine, Sobuzoxane, and Etoposide Is an Effective Option for Relapsed T-cell Prolymphocytic Leukemia with Loss of CD52 Expression after Retreatment with Alemtuzumab. JMA J. 2024 Oct 15;7(4):642-645.
• Ref 4: Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies. Blood. 2022 Nov 17;140(20):2113-2126.
• Ref 5: Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma. Cancers (Basel). 2024 Jun 3;16(11):2130.
• Ref 6: 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.
• 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: Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutationsNat Commun. 2019 Jun 3;10(1):2385. doi: 10.1038/s41467-019-10363-1.
• Ref 9: The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax. Hemato. 2024 Sep;5(3):321-339.
• Ref 10: Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment. Int J Mol Sci. 2023 Aug 23;24(17):13082.