Drug Information

Drug (ID: DG00266) and It's Reported Resistant Information

Name	Bortezomib
Synonyms	179324-69-7; Velcade; Bortezomib (PS-341); UNII-69G8BD63PP; N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE; MLN-341; [(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid; [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid; CHEMBL325041; 69G8BD63PP; Boronic acid,; DPBA; PROSCRIPT BORONIC ACID; LPD 341; LPD-341; VELCADE (TN); Velcade (TN); Pyz-Phe-boroLeu; Bortezomib(JAN/USAN/INN); Velcade, MG-341, PS-341, Bortezomib; N-[(1R)-1-(dihydroxyboranyl)-3-methylbutyl]-Nalpha-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide; Bortezomib (Proteasome inhibitor); Peptide boronate Click to Show/Hide
Indication	In total 3 Indication(s) Mature B-cell lymphoma [ICD-11: 2A85] Approved [1] Multiple myeloma [ICD-11: 2A83] Approved [1] Malignant haematopoietic neoplasm [ICD-11: 2B33] Phase 3 [1]
Structure
Drug Resistance Disease(s)	Disease(s) with Clinically Reported Resistance for This Drug (3 diseases) Cutaneous T-cell lymphoma [ICD-11: 2B00] [2] Mature B-cell neoplasms/lymphoma [ICD-11: 2A85] [4] Multiple myeloma [ICD-11: 2A83] [5], [6] Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases) Cutaneous T-cell lymphomas [ICD-11: 2B00] [3] Multiple myeloma [ICD-11: 2A83] [8]
Target	Cationic trypsinogen (PRSS1)	TRY1_HUMAN	[1]
	Kallikrein-related peptidase (KLK)	NOUNIPROTAC	[1]
	Proteasome (PS)	NOUNIPROTAC	[1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula	C19H25BN4O4
IsoSMILES	B([C@H](CC(C)C)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)C2=NC=CN=C2)(O)O
InChI	1S/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1
InChIKey	GXJABQQUPOEUTA-RDJZCZTQSA-N
PubChem CID	387447
ChEBI ID	CHEBI:52717
TTD Drug ID	D0SH3I
VARIDT ID	DR01331
INTEDE ID	DR0221
DrugBank ID	DB00188

Type(s) of Resistant Mechanism of This Drug

EADR: Epigenetic Alteration of DNA, RNA or Protein

MRAP: Metabolic Reprogramming via Altered Pathways

RTDM: Regulation by the Disease Microenvironment

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Click to Show/Hide the Resistance Disease of This Class

Multiple myeloma [ICD-11: 2A83]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B)				[9]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Multiple myeloma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.30E-09 Fold-change: -7.72E-01 Z-score: -7.50E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	JNk/SAPk signaling pathway		Regulation	N.A.
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.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[11]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Peripheral blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.24E-01 Fold-change: -1.27E-02 Z-score: -4.96E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell colony		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	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: Ubiquitin-conjugating enzyme E2 C (UBE2C)				[12]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Peripheral blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.19E-01 Fold-change: -9.76E-02 Z-score: -6.55E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR631/UbcH10/MDR1 signaling pathway		Regulation	N.A.
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	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)				[22]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	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.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B)				[10]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Multiple myeloma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.30E-09 Fold-change: -7.72E-01 Z-score: -7.50E+00
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-324-5p				[21]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	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				[12]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR631/UbcH10/MDR1 signaling pathway		Regulation	N.A.
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	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: hsa-mir-202				[10]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[22]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	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				[11]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Activation	hsa05200
	Cell viability		Inhibition	hsa05200
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	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				[9]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	JNk/SAPk signaling pathway		Regulation	N.A.
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.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD)				[8]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.85E-04 Fold-change: 1.21E-01 Z-score: 6.68E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	Pentose phosphate signaling pathway		Activation	hsa00030
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	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: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)				[1]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	8226 cells	Bone marrow	Homo sapiens (Human)	CVCL_0014
	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	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: Early growth response protein 1 (EGR1)				[20]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Mutation		.	Molecule Info
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)				[5], [6]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Missense mutation		p.E171K	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
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)				[6]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
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.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-29b-3p				[1]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
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
	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	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]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	8226 cells	Bone marrow	Homo sapiens (Human)	CVCL_0014
	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	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)				[8]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	Pentose phosphate signaling pathway		Activation	hsa00030
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	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.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[7]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Mechanism Description	Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM.
Key Molecule: BCL2 associated X protein (BAX)				[7]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		S1148A	Molecule Info
Mechanism Description	Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM.
Key Molecule: hsa-miR-15a				[13]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	Multiple myeloma patients			Homo sapiens
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay and flow cytometry
Mechanism Description	BMSCs suppress the proliferation of myeloma cells and regulate the drug sensitivity of myeloma cells through the inhibited expression of miRNA-15a/-16.IL-6 plays a pivotal role in the occurrence of drug resistance.
Key Molecule: hsa-miR-33b				[14]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	MM patients			Homo sapiens
Experiment for Molecule Alteration	qRT-PCR
Mechanism Description	Among twenty-five patients with low expression of miR-33b, nine patients received thalidomide-based chemotherapy (Arm A) and fifteen patients received bortezomib-based treatment (Arm B). Strikingly, bortezomib-based treatment did not significantly extend PFS (p = 0.489) and OS (p = 0.586) of patients with miR-33b low expression, suggesting patients with miR-33b down-regulation could be resistant to bortezomib-based treatment.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Tripartite motif containing 44 (TRIM44)				[15]
Metabolic Type	Redox metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
	RPMI cells	Blood	Homo sapiens (Human)	N.A.
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Apoptosis assay
Mechanism Description	This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress.
Key Molecule: Ubiquinone (Q10)				[16]
Metabolic Type	Lipid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	AMO-1 cells	Blood	Homo sapiens (Human)	CVCL_1806
	ARH-77 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1072
	MM RPMI-8226 cells	Blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	Proteomics
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism.
Key Molecule: Pyrroline-5-carboxylate reductase 1 (PYCR1)				[17]
Metabolic Type	Glutamine metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	ANBL-6 cells	Blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	LP-1 cells	Blood	Homo sapiens (Human)	CVCL_0012
	OPM2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis.
Key Molecule: Pyrroline-5-carboxylate reductase 2 (PYCR2)				[17]
Metabolic Type	Glutamine metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	ANBL-6 cells	Blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	LP-1 cells	Blood	Homo sapiens (Human)	CVCL_0012
	OPM2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis.
Key Molecule: Proline-rich Akt substrate 40 kDa (PRAS40)				[17]
Metabolic Type	Glutamine metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	ANBL-6 cells	Blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	LP-1 cells	Blood	Homo sapiens (Human)	CVCL_0012
	OPM2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[18]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	293 T cells	Blood	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS10 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[18]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS6 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[18]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MM1 S cells	Blood	Homo sapiens (Human)	CVCL_8792
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS7 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[18]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	U266B1 cells	Blood	Homo sapiens (Human)	CVCL_0566
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS8 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[18]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS9 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Suppressor of cytokine signaling 6 (SOCS6)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Protein kinase C (PKC)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		.	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Tumor necrosis factor receptor superfamily member 6 (FAS)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Tumor necrosis factor receptor superfamily member 3 (LTBR)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Interleukin-1 receptor-associated kinase 1 (IRAK1)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Stimulator of interferon genes protein (STING1)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.

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

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)		Click to Show/Hide
Key Molecule: CXC chemokine receptor type 4 (CXCR4)			[4]
Resistant Disease	Waldenstrom macroglobulinemia [ICD-11: 2A85.4]		Disease Info
Molecule Alteration	Mutation	.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Mechanism Description	CXCR4 mutation led to bortezomib in the waldenstrom macroglobulinemia.

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

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-187				[23]
Sensitive Disease	Peripheral T-cell lymphoma [ICD-11: 2A90.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MOLT4 cells	Bone marrow	Homo sapiens (Human)	CVCL_0013
	HUT78 cells	Lymph	Homo sapiens (Human)	CVCL_0337
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERk) and AkT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib.
Key Molecule: hsa-miR-125b-1				[24]
Sensitive Disease	Peripheral T-cell lymphoma [ICD-11: 2A90.5]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	cMyc/miR-125b-5p		Regulation	N.A.
In Vitro Model	MyLa2000 cells	Skin	Homo sapiens (Human)	CVCL_8328
	SeAx cells	Skin	Homo sapiens (Human)	CVCL_5363
In Vivo Model	NOD SCID gamma (NSG) mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Chromatin Immunoprecipitation Assay; Western blot
Experiment for Drug Resistance	Apoptosis Assessment
Mechanism Description	Using cutaneous T-cell lymphoma (CTCL) as a model of the chemotherapy-resistant peripheral lymphoid malignancy, we demonstrated that resistance to proteasome inhibition involved a signaling between the oncogene cMyc and miR-125b-5p. Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. Overexpression of cMyc repressed miR-125b-5p transcription and sensitized lymphoma cells to bortezomib. The central role of miR-125b-5p was further confirmed in a mouse model of T-cell lymphoma, where xenotransplantation of human CTCL cells overexpressing miR-125b-5p resulted in enhanced tumor growth and a shorter median survival. Our findings describe a novel mechanism through which miR-125b-5p not only regulates tumor growth in vivo, but also increases cellular resistance to proteasome inhibitors via modulation of MAD4.

Cutaneous T-cell lymphoma [ICD-11: 2B00]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-125b-5p				[2]
Resistant Disease	Cutaneous T-cell lymphomas [ICD-11: 2B00.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
In Vitro Model	MyLa2000 cells	Skin	Homo sapiens (Human)	CVCL_8328
	SeAx cells	Skin	Homo sapiens (Human)	CVCL_5363
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. miR-125b-5p can regulates tumor growth in vivo,and increases cellular resistance to proteasome inhibitors via modulation of MAD4.
Key Molecule: hsa-miR-122				[3]
Resistant Disease	Cutaneous T-cell lymphomas [ICD-11: 2B00.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	p53/AKT Signalling		Regulation	N.A.
In Vitro Model	MyLa2000 cells	Skin	Homo sapiens (Human)	CVCL_8328
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	Flow cytometry assays
Mechanism Description	We found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers (bortezomib, MG132). miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sezary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Max dimerization protein 4 (MXD4)				[2]
Resistant Disease	Cutaneous T-cell lymphomas [ICD-11: 2B00.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
In Vitro Model	MyLa2000 cells	Skin	Homo sapiens (Human)	CVCL_8328
	SeAx cells	Skin	Homo sapiens (Human)	CVCL_5363
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. miR-125b-5p can regulates tumor growth in vivo,and increases cellular resistance to proteasome inhibitors via modulation of MAD4.

Osteosarcoma [ICD-11: 2B51]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-101				[25]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Proteasome maturation protein (POMP)				[25]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Colon cancer [ICD-11: 2B90]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-101				[25]
Sensitive Disease	Colon carcinoma [ICD-11: 2B90.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Proteasome maturation protein (POMP)				[25]
Sensitive Disease	Colon carcinoma [ICD-11: 2B90.2]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Liver cancer [ICD-11: 2C12]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-101				[25]
Sensitive Disease	Hepatocellular cancer [ICD-11: 2C12.4]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Proteasome maturation protein (POMP)				[25]
Sensitive Disease	Hepatocellular cancer [ICD-11: 2C12.4]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Breast cancer [ICD-11: 2C60]

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Drug Sensitive Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-101-1				[26]
Sensitive Disease	Breast cancer [ICD-11: 2C60.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Ubiquitin-proteasome pathway		Regulation	N.A.
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
Experiment for Molecule Alteration	qRT-PCR
Mechanism Description	In ERalpha-positive breast cancers, miR-101 and POMP levels are inversely correlated, and high miR-101 expression or low POMP expression associates with prolonged survival. Mechanistically, miR-101 expression or POMP knockdown attenuated estrogen-driven transcription. Finally, suppressing POMP is sufficient to overcome tumor cell resistance to the proteasome inhibitor bortezomib.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-let-7a-5p				[27]
Sensitive Disease	Breast cancer [ICD-11: 2C60.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	BT-20 cells	Mammary gland	Homo sapiens (Human)	CVCL_0178
	BT-474 cells	Breast	Homo sapiens (Human)	CVCL_0179
	BT-549 cells	Breast	Homo sapiens (Human)	CVCL_1092
	CAMA-1 cells	Breast	Homo sapiens (Human)	CVCL_1115
	HCC1143 cells	Breast	Homo sapiens (Human)	CVCL_1245
	HCC1806 cells	Breast	Homo sapiens (Human)	CVCL_1258
	HCC1937 cells	Breast	Homo sapiens (Human)	CVCL_0290
	HCC1954 cells	Breast	Homo sapiens (Human)	CVCL_1259
	HCC38 cells	Breast	Homo sapiens (Human)	CVCL_1267
	HCC70 cells	Breast	Homo sapiens (Human)	CVCL_1270
	Hs578T cells	Breast	Homo sapiens (Human)	CVCL_0332
	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	MDA-MB-361 cells	Breast	Homo sapiens (Human)	CVCL_0620
	MDA-MB-436 cells	Breast	Homo sapiens (Human)	CVCL_0623
	MDA-MB-468 cells	Breast	Homo sapiens (Human)	CVCL_0419
	SK-BR-3 cells	Pleural effusion	Homo sapiens (Human)	CVCL_0033
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	EVSA-T cells	Ascites	Homo sapiens (Human)	CVCL_1207
	Sk-BR-7 cells	Breast	Homo sapiens (Human)	CVCL_5218
	SUM159PT cells	Breast	Homo sapiens (Human)	CVCL_5423/CVCL_5590
	SUM44PE cells	Breast	Homo sapiens (Human)	CVCL_3424
	SUM52PE cells	Breast	Homo sapiens (Human)	CVCL_3425
Experiment for Molecule Alteration	Microarray analyses
Mechanism Description	This gene is up-regulated in bortezomib-sensitive cells

Cervical cancer [ICD-11: 2C77]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-101				[25]
Sensitive Disease	Cervical cancer [ICD-11: 2C77.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Proteasome maturation protein (POMP)				[25]
Sensitive Disease	Cervical cancer [ICD-11: 2C77.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

References

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Prof. Feng ZHU (zhufeng@zju.edu.cn)