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]
• Resistant Drug: Bendamustine hydrochloride
• Molecule Alteration: Mutation; .
• 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]
• Resistant Drug: Bortezomib
• Molecule Alteration: Mutation; .
• 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]
• Resistant Drug: Copanlisib
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Resistant Drug: Dexamethasone
• Molecule Alteration: Expression; Up-regulation
• 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]
• Resistant Drug: Dexamethasone
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Resistant Drug: Dexamethasone
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Sensitive Drug: Dexamethasone
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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]
• Sensitive Drug: Dexamethasone
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• 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]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• 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]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• 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]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [7]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RAJI/DOX cells; Blood; Homo sapiens (Human); N.A.
• Mechanism Description: The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

Key Molecule: AKT serine/threonine kinase (AKT) [7]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RAJI/DOX cells; Blood; Homo sapiens (Human); N.A.
• Mechanism Description: The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

Key Molecule: Glycerol-3-phosphate phosphatase (PGP) [7]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RAJI/DOX cells; Blood; Homo sapiens (Human); N.A.
• Mechanism Description: The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

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]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• 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]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Up-regulation
• 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]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Down-regulation
• 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]
• Resistant Drug: Fludarabine
• Molecule Alteration: Mutation; .
• 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) [8]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481S
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.40 Å; PDB: 6VXQ
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.33 Å; PDB: 8FLN

RMSD: 0.82; TM score: 0.96927; Amino acid change: C481S

• 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]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481S
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.40 Å; PDB: 6VXQ
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.33 Å; PDB: 8FLN

RMSD: 0.82; TM score: 0.96927; Amino acid change: C481S

• 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) [9]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481S
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.40 Å; PDB: 6VXQ
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.33 Å; PDB: 8FLN

RMSD: 0.82; TM score: 0.96927; Amino acid change: C481S

• 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]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.Y361C
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.G123S
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.D357E
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.D230N
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Mutation; .
• 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) [9]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Mutation; p.S338X
• 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) [9]

• Sensitive Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Sensitive Drug: Ibrutinib
• Molecule Alteration: Mutation; p.L265P
• 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]
• Resistant Drug: Idelalisib
• Molecule Alteration: Mutation; .
• 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]
• Resistant Drug: IPI-145
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Missense mutation; p.Y361C
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Missense mutation; p.G123S
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Missense mutation; p.D357E
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Missense mutation; p.D230N
• 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) [10]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Resistant Drug: Melphalan
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Resistant Drug: Melphalan
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Sensitive Drug: Melphalan
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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]
• Sensitive Drug: Melphalan
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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) [11]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Sirolimus
• Molecule Alteration: Expression; Down-regulation
• 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; N.A.
• 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) [11]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Sirolimus
• Molecule Alteration: Expression; Down-regulation
• 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; N.A.
• 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) [11]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Temsirolimus
• Molecule Alteration: Expression; Down-regulation
• 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; N.A.
• 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]
• Resistant Drug: Topotecan
• Molecule Alteration: Expression; Up-regulation
• 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]
• Resistant Drug: Topotecan
• Molecule Alteration: Expression; Down-regulation
• 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]
• Resistant Drug: Vincristine
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Resistant Drug: Vincristine
• Molecule Alteration: Expression; Up-regulation
• 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 blot 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]
• Sensitive Drug: Vincristine
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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]
• Sensitive Drug: Vincristine
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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.

Clinical Trial Drug(s) 1 drug(s) in total

Dactolisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [7]

• Sensitive Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Sensitive Drug: Dactolisib
• Molecule Alteration: Phosphorylation; S704
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RAJI/DOX cells; Blood; Homo sapiens (Human); N.A.
• Mechanism Description: The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

Key Molecule: AKT serine/threonine kinase (AKT) [7]

• Sensitive Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Sensitive Drug: Dactolisib
• Molecule Alteration: Phosphorylation; T1080S
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RAJI/DOX cells; Blood; Homo sapiens (Human); N.A.
• Mechanism Description: The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

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

BTK inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor tyrosine-protein kinase erbB-4 (ERBB4) [12]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: BTK inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

Key Molecule: Proheparin-binding EGF-like growth factor (HBEGF) [12]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: BTK inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

Key Molecule: Pro-neuregulin-2, membrane-bound isoform (NRG2) [12]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: BTK inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

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) [13]

• Sensitive Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Sensitive Drug: IMG-2005-5
• Molecule Alteration: Missense mutation; p.L265P (c.794T>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; N.A.
• 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) 3 drug(s) in total

Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatidylinositol 3-kinase (PI3K) [14]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Phosphatidylinositol 3-kinase gamma; Regulation; N.A.
• In Vitro Model: TS cells; Head and Neck; Homo sapiens (Human); CVCL_VH06
• In Vitro Model: SU-DHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0538
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: JB6 [Human anaplastic large cell lymphoma] cells; Lymphoid; Homo sapiens (Human); CVCL_H633
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vitro Model: DEL cells; Pleural effusion; Homo sapiens (Human); CVCL_1170
• In Vitro Model: L-82 cells; Pleural effusion; Homo sapiens (Human); CVCL_2098
• In Vitro Model: Mac-1 cells; Lymph; Homo sapiens (Human); CVCL_H631
• In Vitro Model: FE-PD cells; Lymph; Homo sapiens (Human); CVCL_H614
• In Vitro Model: CEM cells; Lymph; Homo sapiens (Human); N.A.
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: Murine cells; Lymph; Homo sapiens (Human); N.A.
• In Vivo Model: CD4-NPM-ALK xenograft mice model; PI3KgammaCX/CX xenograft mice model; PI3Kgamma-/- xenograft mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; Fluorescence in situ hybridization assay; Histology assay; Immunohistochemistry; qRT-PCR; Flow cytometry
• Experiment for Drug Resistance: Cell proliferation assay; Apoptosis assay; Cell viability assay; Drug sensitivity assay; Chemokine assay
• Mechanism Description: Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase gamma (PI3K-gamma) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kgamma expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kgamma, and PI3Kdelta were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kgamma isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kgamma/delta inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kgamma or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

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) [13]

• Sensitive Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Sensitive Drug: IRAK-1 or IRAK-4 inhibitors
• Molecule Alteration: Missense mutation; p.L265P (c.794T>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; N.A.
• 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

PI3K inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor tyrosine-protein kinase erbB-4 (ERBB4) [12]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: PI3K inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

Key Molecule: Proheparin-binding EGF-like growth factor (HBEGF) [12]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: PI3K inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

Key Molecule: Pro-neuregulin-2, membrane-bound isoform (NRG2) [12]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: PI3K inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

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