Disease Information

General Information of the Disease (ID: DIS00057)

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

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 16 drug(s) in total

Bendamustine hydrochloride

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [1]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; .
• Resistant Drug: Bendamustine hydrochloride
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to bendamustine in the waldenstrom macroglobulinemia.

Bortezomib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [1]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; .
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to bortezomib in the waldenstrom macroglobulinemia.

Copanlisib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin 6 receptor (IL6R) [2]

• Resistant Disease: Non-Hodgkin lymphoma [ICD-11: 2A85.5]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Copanlisib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vitro Model: C4-2B cells; Prostate; Homo sapiens (Human); CVCL_4784
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• In Vitro Model: Riva cells; Pleural effusion; Homo sapiens (Human); N.A.
• In Vitro Model: SU-DHL2 cells; Pleural effusion; Homo sapiens (Human); CVCL_9550
• In Vitro Model: U2932 (ABC-DLBCL) cells; Ascites; Homo sapiens (Human); CVCL_1896
• In Vitro Model: BJAB cells; Groin; Homo sapiens (Human); CVCL_5711
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-kappaB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects.IL-6-induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.

Dexamethasone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: ROR1 antisense RNA 1 (ROR1-AS1) [3]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Granta cells; Peripheral blood; Homo sapiens (Human); N.A.
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: Overexpression of ROR1-AS1 LncRNA promoted growth of MCL cells while decreased sensitivity to the treatment with drugs ibrutinib and dexamethasone.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [4]

• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [4]

• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-17-92 [5]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Z138c cells; Blood; Homo sapiens (Human); CVCL_B077
• In Vivo Model: CB-17/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Xenograft experiments assay
• Mechanism Description: The protein phosphatase PHLPP2, an important negative regulator of the PI3k/AkT pathway, was a direct target of miR-17 92 miRNAs, miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3k/AkT pathway activation.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Fructose-bisphosphatase 1 (FBP1) [6]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: OCI-LY8 cells; Oral; Homo sapiens (Human); CVCL_8803
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• Experiment for Molecule Alteration: Immunoblot analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Cell adhesion mediated drug resistance (CAM DR) remains a major obstacle to the effectiveness of chemotherapeutic treatment of lymphoma. Far upstream element binding protein 1 (FBP1) is a multifunctional protein that is highly expressed in proliferating cells of several solid neoplasms. CAM-DR is considered a major mechanism by which tumor cells escape the cytotoxic effects of therapeutic agents.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2) [5]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Z138c cells; Blood; Homo sapiens (Human); CVCL_B077
• In Vivo Model: CB-17/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: Xenograft experiments assay
• Mechanism Description: The protein phosphatase PHLPP2, an important negative regulator of the PI3k/AkT pathway, was a direct target of miR-17 92 miRNAs, miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3k/AkT pathway activation.

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [4]

• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Fructose-bisphosphatase 1 (FBP1) [6]

• Sensitive Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: OCI-LY8 cells; Oral; Homo sapiens (Human); CVCL_8803
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• Experiment for Molecule Alteration: Immunoblot analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Cell adhesion mediated drug resistance (CAM DR) remains a major obstacle to the effectiveness of chemotherapeutic treatment of lymphoma. Far upstream element binding protein 1 (FBP1) is a multifunctional protein that is highly expressed in proliferating cells of several solid neoplasms. CAM-DR is considered a major mechanism by which tumor cells escape the cytotoxic effects of therapeutic agents.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [4]

• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-17-92 [5]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Z138c cells; Blood; Homo sapiens (Human); CVCL_B077
• In Vivo Model: CB-17/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Xenograft experiments assay
• Mechanism Description: The protein phosphatase PHLPP2, an important negative regulator of the PI3k/AkT pathway, was a direct target of miR-17 92 miRNAs, miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3k/AkT pathway activation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2) [5]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Z138c cells; Blood; Homo sapiens (Human); CVCL_B077
• In Vivo Model: CB-17/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: Xenograft experiments assay
• Mechanism Description: The protein phosphatase PHLPP2, an important negative regulator of the PI3k/AkT pathway, was a direct target of miR-17 92 miRNAs, miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3k/AkT pathway activation.

Fludarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [1]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; .
• Resistant Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to fludarabine in the waldenstrom macroglobulinemia.

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase BTK (BTK) [7]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.C481S
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mantle cell lymphoma isolates; Peripheral blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-transcriptome sequencing assay
• Mechanism Description: This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary-resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance.

Key Molecule: Tyrosine-protein kinase BTK (BTK) [7]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.C481S
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mantle cell lymphoma isolates; Peripheral blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-transcriptome sequencing assay
• Mechanism Description: This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary-resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance.

Key Molecule: Tyrosine-protein kinase BTK (BTK) [8]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.C481S
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PIK3/AKT signaling pathway; Activation; hsa04211
• Mechanism Description: Efforts have been made to understand the functional consequences of the BTK mutation. On a structural level, the C481S mutation disrupts covalent binding, allowing for reversible, instead of strong irreversible, binding of BTK by ibrutinib. The critical biochemical role of covalent-bond formation was revealed when fluorescently tagged-ibrutinib labelled the wild-type (WT) BTK, but not the BTKC481S mutant.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: ROR1 antisense RNA 1 (ROR1-AS1) [3]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ibrutinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Granta cells; Peripheral blood; Homo sapiens (Human); N.A.
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: Overexpression of ROR1-AS1 LncRNA promoted growth of MCL cells while decreased sensitivity to the treatment with drugs ibrutinib and dexamethasone.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.Y361C
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.G123S
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.D357E
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.D230N
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [1]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; .
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to ibrutinib in the waldenstrom macroglobulinemia.

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [8]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; p.S338X
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Mechanism Description: CXCR4 is a transmembrance chemokine receptor that is internalized upon binding to its ligand CXCL12 and subsequently signals through G-proteins to activate the AKT and ERK pathways. The CXCR4 pathway plays an important role in lymphocyte migration and homing. CXCR4WHIM-like are prevalent somatic mutations, present in 30% of patients with WM. It was recently demonstrated that CXCR4S338X, the most common WHIM-like mutation, reduces CXCR4 receptor internalization and allows for sustained enzymatic activity of AKT and ERK and subsequent increased cell survival. When cells are exposed to ibrutinb, CXCR4S338X-carrying WM cells, compared to CXCR4WT cells, exhibit reduced apoptosis.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myeloid differentiation primary response protein MyD88 (MYD88) [8]

• Sensitive Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; p.L265P
• Sensitive Drug: Ibrutinib
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The mutant, as opposed to MYD88WT, preferentially binds to p-BTK and subsequently activates NFKB. Ibrutinib treatment reduces such binding, therefore blocking downstream NFKB activation. Thus, the oncogenic activity of MYD88L265P is mediated through BTK in WM and renders cells sensitive to ibrutinib's inhibition. The fact that MYD88 mutations function differently in different cells highlight the notion that impact of a particular genetic mutation has to be determined and understood within the particular cellular context.

Idelalisib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [1]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; .
• Resistant Drug: Idelalisib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to idelalisib in the waldenstrom macroglobulinemia.

IPI-145

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin 6 receptor (IL6R) [2]

• Resistant Disease: Non-Hodgkin lymphoma [ICD-11: 2A85.5]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: IPI-145
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vitro Model: C4-2B cells; Prostate; Homo sapiens (Human); CVCL_4784
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• In Vitro Model: Riva cells; Pleural effusion; Homo sapiens (Human); N.A.
• In Vitro Model: SU-DHL2 cells; Pleural effusion; Homo sapiens (Human); CVCL_9550
• In Vitro Model: U2932 (ABC-DLBCL) cells; Ascites; Homo sapiens (Human); CVCL_1896
• In Vitro Model: BJAB cells; Groin; Homo sapiens (Human); CVCL_5711
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-kappaB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects.IL-6-induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.

Lenalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.Y361C
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.G123S
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.D357E
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.D230N
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Melphalan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [4]

• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [4]

• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Sirolimus

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Growth arrest specific 5 (GAS5) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sirolimus
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Nigrosin exclusion analysis
• Mechanism Description: Small interfering RNAs (sirRNAs) targeting GAS5 protect the cell viability and proliferation of jeko-1 and z-138 cells from the inhibitory effects of mTOR inhibitors result in rapamycin resistance.

Key Molecule: Growth arrest specific 5 (GAS5) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sirolimus
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Nigrosin exclusion analysis
• Mechanism Description: Small interfering RNAs (sirRNAs) targeting GAS5 protect the cell viability and proliferation of jeko-1 and z-138 cells from the inhibitory effects of mTOR inhibitors result in rapamycin resistance.

Temsirolimus

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Growth arrest specific 5 (GAS5) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temsirolimus
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Nigrosin exclusion analysis
• Mechanism Description: Small interfering RNAs (sirRNAs) targeting GAS5 protect the cell viability and proliferation of jeko-1 and z-138 cells from the inhibitory effects of mTOR inhibitors result in rapamycin resistance.

Topotecan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-17-92 [5]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Topotecan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Z138c cells; Blood; Homo sapiens (Human); CVCL_B077
• In Vivo Model: CB-17/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Xenograft experiments assay
• Mechanism Description: The protein phosphatase PHLPP2, an important negative regulator of the PI3k/AkT pathway, was a direct target of miR-17 92 miRNAs, miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3k/AkT pathway activation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2) [5]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Topotecan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Z138c cells; Blood; Homo sapiens (Human); CVCL_B077
• In Vivo Model: CB-17/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: Xenograft experiments assay
• Mechanism Description: The protein phosphatase PHLPP2, an important negative regulator of the PI3k/AkT pathway, was a direct target of miR-17 92 miRNAs, miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3k/AkT pathway activation.

Vincristine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [4]

• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [4]

• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

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

IMG-2005-5

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myeloid differentiation primary response protein MyD88 (MYD88) [11]

• Sensitive Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.L265P (c.794T>C)
• Sensitive Drug: IMG-2005-5
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; .
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.L265P (c.794T>C) in gene MYD88 cause the sensitivity of IMG-2005-5 by unusual activation of pro-survival pathway

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

IRAK-1 or IRAK-4 inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myeloid differentiation primary response protein MyD88 (MYD88) [11]

• Sensitive Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.L265P (c.794T>C)
• Sensitive Drug: IRAK-1 or IRAK-4 inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; .
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.L265P (c.794T>C) in gene MYD88 cause the sensitivity of IRAK-1 or IRAK-4 inhibitors by unusual activation of pro-survival pathway

References

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• Ref 2: Interleukin-6 mediates resistance to PI3K-pathway-targeted therapy in lymphoma .BMC Cancer. 2019 Oct 10;19(1):936. doi: 10.1186/s12885-019-6057-7. 10.1186/s12885-019-6057-7
• Ref 3: Long non-coding RNA profile in mantle cell lymphoma identifies a functional lncRNA ROR1-AS1 associated with EZH2/PRC2 complex. Oncotarget. 2017 May 17;8(46):80223-80234. doi: 10.18632/oncotarget.17956. eCollection 2017 Oct 6.
• Ref 4: Dasatinib reverses drug resistance by downregulating MDR1 and Survivin in Burkitt lymphoma cells .BMC Complement Med Ther. 2020 Mar 14;20(1):84. doi: 10.1186/s12906-020-2879-8. 10.1186/s12906-020-2879-8
• Ref 5: The miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia. 2012 May;26(5):1064-72. doi: 10.1038/leu.2011.305. Epub 2011 Nov 25.
• Ref 6: Expression of far upstream element binding protein 1 in B cell non Hodgkin lymphoma is correlated with tumor growth and cell adhesion mediated drug resistance .Mol Med Rep. 2016 Oct;14(4):3759-68. doi: 10.3892/mmr.2016.5718. Epub 2016 Sep 6. 10.3892/mmr.2016.5718
• Ref 7: Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects .Br J Haematol. 2018 May;181(3):306-319. doi: 10.1111/bjh.15108. Epub 2018 Jan 23. 10.1111/bjh.15108
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