Disease Information

General Information of the Disease (ID: DIS00056)

• Name: Multiple myeloma
• ICD: ICD-11: 2A83

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 11 drug(s) in total

Bortezomib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-29b-3p [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 8226 cells; Bone marrow; Homo sapiens (Human); CVCL_0014
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via downregulating miR-29b-3p.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 8226 cells; Bone marrow; Homo sapiens (Human); CVCL_0014
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p.

Key Molecule: Protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) [2]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Pentose phosphate signaling pathway; Activation; hsa00030
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, leading to increase of G6PD expression and PPP flux, promoting cell proliferation and drug resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 8226 cells; Bone marrow; Homo sapiens (Human); CVCL_0014
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via downregulating miR-29b-3p.

Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD) [2]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Pentose phosphate signaling pathway; Activation; hsa00030
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, leading to increase of G6PD expression and PPP flux, promoting cell proliferation and drug resistance.

Key Molecule: Early growth response protein 1 (EGR1) [3]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Exome sequencing assay; High-resolution copy-number array assay; Cytogenetics exome sequencing assay
• Mechanism Description: Knockdown of EGR1 in myeloma cells enhanced their resistance to bortezomib, and the clustered point mutation of key residues that we observed may have similar effects.

Key Molecule: Proteasome assembly chaperone 2 (PSMG2) [4], [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.E171K
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Proteasome subunit beta type-5 (PSMB5) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-324-5p [6]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Inhibition; hsa04340
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: ARH-77 cells; Peripheral blood; Homo sapiens (Human); CVCL_1072
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Colony formation assay
• Mechanism Description: Overexpression of miR324-5p significantly decreased Hh signaling components Smo and Gli1, and functionally reduced cell growth, survival as well as stem cell compartment in MM. miR324-5p potentiated the anti-MM efficacy of bortezomib through regulating the activities of multidrug-resistance proteins and the expression of Bcl-2 family genes. Down-regulation of miR324-5p is a novel mechanism of Hh signaling activation in MM.

Key Molecule: hsa-miR-631 [7]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR631/UbcH10/MDR1 signaling pathway; Regulation; hsa05206
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hsa-miR631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10.

Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B) [8]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Activation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay; Annexin V-FLUOS assay
• Mechanism Description: miR202 contributes to sensitizing MM cells to drug significantly via activing JNk/SAPk signaling pathway. miR202 mimics combined with Bort could inhibit proliferation and induce apoptosis of U266 cells through negative regulating target gene BAFF, which further inhibited the JNk/SAPk signaling pathway.

Key Molecule: hsa-mir-202 [8]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Activation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay; Annexin V-FLUOS assay
• Mechanism Description: miR202 contributes to sensitizing MM cells to drug significantly via activing JNk/SAPk signaling pathway. miR202 mimics combined with Bort could inhibit proliferation and induce apoptosis of U266 cells through negative regulating target gene BAFF, which further inhibited the JNk/SAPk signaling pathway.

Key Molecule: hsa-mir-137 [9]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Epigenetic silencing of miR137 induces drug resistance and chromosomal instability by targeting AURkA in multiple myeloma.

Key Molecule: hsa-mir-497 [10]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2.

Key Molecule: hsa-mir-202 [11]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Regulation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ubiquitin-conjugating enzyme E2 C (UBE2C) [7]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR631/UbcH10/MDR1 signaling pathway; Regulation; hsa05206
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hsa-miR631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10.

Key Molecule: Aurora kinase A (AURKA) [9]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Epigenetic silencing of miR137 induces drug resistance and chromosomal instability by targeting AURkA in multiple myeloma.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [10]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2.

Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B) [11]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Regulation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST assay
• Mechanism Description: miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Dexamethasone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [12]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: ANBL6 cells; Peripheral blood; Homo sapiens (Human); CVCL_5425
• In Vitro Model: JJN-3 cells; Bone marrow; Homo sapiens (Human); CVCL_2078
• In Vitro Model: MM1R cells; Peripheral blood; Homo sapiens (Human); CVCL_8794
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR193a/MCL1 pathway. NEAT1 promotes MM cell DEX resistance by competitively binding miR193a.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-15 [13]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: microRNA-15a and -16 expressions tightly correlated with proliferation and drug sensitivity of MM cells. miRNA-15a/-16 expression in MM cells was significantly increased after treatment with cytotoxic agents. The interaction of bone marrow stromal cells (BMSC) with MM cells resulted in decreased miRNA-15a/-16 expression and promoted the survival of the MM cells.

Key Molecule: hsa-mir-16 [13]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: microRNA-15a and -16 expressions tightly correlated with proliferation and drug sensitivity of MM cells. miRNA-15a/-16 expression in MM cells was significantly increased after treatment with cytotoxic agents. The interaction of bone marrow stromal cells (BMSC) with MM cells resulted in decreased miRNA-15a/-16 expression and promoted the survival of the MM cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [12]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: ANBL6 cells; Peripheral blood; Homo sapiens (Human); CVCL_5425
• In Vitro Model: JJN-3 cells; Bone marrow; Homo sapiens (Human); CVCL_2078
• In Vitro Model: MM1R cells; Peripheral blood; Homo sapiens (Human); CVCL_8794
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR193a/MCL1 pathway. NEAT1 promotes MM cell DEX resistance by competitively binding miR193a.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-193a [12]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR193a/MCL1 signaling pathway; Activation; hsa05206
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: ANBL6 cells; Peripheral blood; Homo sapiens (Human); CVCL_5425
• In Vitro Model: JJN-3 cells; Bone marrow; Homo sapiens (Human); CVCL_2078
• In Vitro Model: MM1R cells; Peripheral blood; Homo sapiens (Human); CVCL_8794
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR193a/MCL1 pathway.

Key Molecule: hsa-mir-137 [14]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vivo Model: BALB/c nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Real Time RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-137 can improve the dexamethasone sensitivity in multiple myeloma cells by reducing the c-MET expression and further decreasing the AkT phosphorylation via targeting MITF.

Key Molecule: hsa-mir-202 [11]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Regulation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Microphthalmia-associated transcription factor (MITF) [14]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-137 can improve the dexamethasone sensitivity in multiple myeloma cells by reducing the c-MET expression and further decreasing the AkT phosphorylation via targeting MITF.

Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B) [11]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Regulation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST assay
• Mechanism Description: miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-155 [15]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: RPMI8226/Dox cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: RPMI8226/S cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Targeting inhibition of miR155 expression could restore chemotherapy sensitivity by increasing FOXO3a expression in drug-resistant myeloma cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box protein O3 (FOXO3) [15]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: RPMI8226/Dox cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: RPMI8226/S cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Targeting inhibition of miR155 expression could restore chemotherapy sensitivity by increasing FOXO3a expression in drug-resistant myeloma cells.

Epirubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-137 [9]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Epirubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Ectopic expression of miR137 strongly reduced the expression of AURkA and p-ATM/Chk2 in MM cells, and increased the expression of p53, and p21, overexpression of miR137 could reduce drug resistance and overcome chromosomal instability of the MM cells via affecting the apoptosis and RNA damage pathways.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Aurora kinase A (AURKA) [9]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Epirubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Ectopic expression of miR137 strongly reduced the expression of AURkA and p-ATM/Chk2 in MM cells, and increased the expression of p53, and p21, overexpression of miR137 could reduce drug resistance and overcome chromosomal instability of the MM cells via affecting the apoptosis and RNA damage pathways.

Iopamidol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Solute carrier family 2, facilitated glucose transporter member 1 (Glucose transporter type 1, erythrocyte/brain) (GLUT-1) (GT1) [16]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Iopamidol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vivo Model: Orthotopic BM engrafted MM xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemistry and histologic analysis
• Experiment for Drug Resistance: Micro-Computed Tomography; Positron emission tomography; Magnetic resonance spectroscopy; Magnetic resonance imaging (MRI)
• Mechanism Description: Adaptive responses to hypoxia may be an essential element in MM progression and drug resistance. This metabolic adaptation involves a decrease in extracellular pH (pHe), and it depends on the upregulation of glucose transporters (GLUTs) that is common in hypoxia and in cancer cells.

Lenalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger protein Aiolos (IKZF3) [17], [18]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.Q147H
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Zinc finger protein Helios (IKZF2) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: DNA-binding protein Ikaros (IKZF1) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: DNA damage-binding protein 1 (DDB1) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Cullin-4B (CUL4B) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Cullin-4A (CUL4A) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Protein cereblon (CRBN) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Truncating mutation; p.Q99*
• Resistant Drug: Lenalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Melphalan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA (LINC00515) [19]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Key Molecule: hsa-miR-140-5p [19]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Key Molecule: hsa-mir-221 [20]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beclin 1-associated autophagy-related key regulator (ATG14) [19]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Key Molecule: Bcl-2-binding component 3 (BBC3) [20]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.

Key Molecule: Bcl-2-binding component 3 (BBC3) [20]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-140-5p [19]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beclin 1-associated autophagy-related key regulator (ATG14) [19]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Melphalan
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Pomalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Protein cereblon (CRBN) [21]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Pomalidomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Mechanism Description: Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma.

Thalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger protein Aiolos (IKZF3) [17], [18]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.Q147H
• Resistant Drug: Thalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Zinc finger protein Helios (IKZF2) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Thalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: DNA-binding protein Ikaros (IKZF1) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Thalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: DNA damage-binding protein 1 (DDB1) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Thalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Cullin-4B (CUL4B) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Thalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Cullin-4A (CUL4A) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Thalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Protein cereblon (CRBN) [4], [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Truncating mutation; p.R283K
• Resistant Drug: Thalidomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-202 [11]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Thalidomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Regulation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B) [11]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Thalidomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Regulation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST assay
• Mechanism Description: miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Trifluoperazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Nuclear protein 1, transcriptional regulator (NUPR1) [22]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Trifluoperazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HSC3 cells; Tongue; Homo sapiens (Human); CVCL_1288
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: There was statistical difference in the expression of the aforementioned proteins between the TFptreated group and TFptreated NC-LV group, but the autophagy level was upregulated and apoptosis was downregulated in the TFptreated NUPR1-LV group compared with the TFptreated NC-LV group. NUPR1 overexpression reversed the autophagic suppression and cellular apoptosis induction caused by TFP in U266 and RPMI 8226 cells. Thus, we concluded that TFP targeted NUPR1 in MM cells and subsequently induced apoptosis by inhibiting autophagy.

Vemurafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [23]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.Q61H
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Ion Torrent semiconductor-based targeted resequencing assay
• Experiment for Drug Resistance: Whole-body magnetic resonance imaging (MRI) assay
• Mechanism Description: Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).

Key Molecule: GTPase Nras (NRAS) [23]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.G13R
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Ion Torrent semiconductor-based targeted resequencing assay
• Experiment for Drug Resistance: Whole-body magnetic resonance imaging (MRI) assay
• Mechanism Description: Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).

Key Molecule: GTPase Nras (NRAS) [23]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.G12A
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Ion Torrent semiconductor-based targeted resequencing assay
• Experiment for Drug Resistance: Whole-body magnetic resonance imaging (MRI) assay
• Mechanism Description: Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).

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

E7090

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [24]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Drug: E7090
• Experimental Note: Identified from the Human Clinical Data

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

Cortiosteroids

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proteasome assembly chaperone 2 (PSMG2) [4], [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.E171K
• Resistant Drug: Cortiosteroids
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Proteasome subunit beta type-5 (PSMB5) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Cortiosteroids
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

References

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