Disease Information

General Information of the Disease (ID: DIS00218)

• Name: Metastatic bone cancer
• ICD: ICD-11: 2E03

Type(s) of Resistant Mechanism of This Disease

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Resistant Disease: Breast cancer bone metastasis [ICD-11: 2E03.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometric
• Mechanism Description: Studies have shown that resistance can occur from altered expression of apoptosis regulatory proteins (p53, Bcl-2), and overexpression of ATP binding cassette (ABC) transporters/ multidrug resistance-related proteins such as multidrug resistance-associated protein 1 (MRP1), ATP-binding cassette super-family G member 2 (ABCG2).

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [1]

• Resistant Disease: Breast cancer bone metastasis [ICD-11: 2E03.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometric
• Mechanism Description: Studies have shown that resistance can occur from altered expression of apoptosis regulatory proteins (p53, Bcl-2), and overexpression of ATP binding cassette (ABC) transporters/ multidrug resistance-related proteins such as multidrug resistance-associated protein 1 (MRP1), ATP-binding cassette super-family G member 2 (ABCG2).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [1]

• Resistant Disease: Breast cancer bone metastasis [ICD-11: 2E03.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometric
• Mechanism Description: Interleukin-6 (IL-6), a pro-inflammatory cytokine produced in the tumor microenvironment by stromal cells, fibroblasts, and cancer cells. Binding of IL-6 to its receptor IL-6R on the cell membrane activates Janus Kinase 2 (JAK2) kinases. Activated JAK2 mediates phosphorylation, dimerization, and nuclear translocation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 signaling mediates the expression of various genes, including p53, Bcl-2, MRP1, and ABCG2. Bcl-2 and p53 are associated with regulation of apoptosis while overexpression of drug transporters MRP1, ABCG2 has been shown to mediate efflux of drugs from cancer cells, thus decreasing intracellular drug concentration leading to drug-resistance.

Key Molecule: Interleukin 6 receptor (IL6R) [1]

• Resistant Disease: Breast cancer bone metastasis [ICD-11: 2E03.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometric
• Mechanism Description: Interleukin-6 (IL-6), a pro-inflammatory cytokine produced in the tumor microenvironment by stromal cells, fibroblasts, and cancer cells. Binding of IL-6 to its receptor IL-6R on the cell membrane activates Janus Kinase 2 (JAK2) kinases. Activated JAK2 mediates phosphorylation, dimerization, and nuclear translocation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 signaling mediates the expression of various genes, including p53, Bcl-2, MRP1, and ABCG2. Bcl-2 and p53 are associated with regulation of apoptosis while overexpression of drug transporters MRP1, ABCG2 has been shown to mediate efflux of drugs from cancer cells, thus decreasing intracellular drug concentration leading to drug-resistance.

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Resistant Disease: Breast cancer bone metastasis [ICD-11: 2E03.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometric
• Mechanism Description: Interleukin-6 (IL-6), a pro-inflammatory cytokine produced in the tumor microenvironment by stromal cells, fibroblasts, and cancer cells. Binding of IL-6 to its receptor IL-6R on the cell membrane activates Janus Kinase 2 (JAK2) kinases. Activated JAK2 mediates phosphorylation, dimerization, and nuclear translocation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 signaling mediates the expression of various genes, including p53, Bcl-2, MRP1, and ABCG2. Bcl-2 and p53 are associated with regulation of apoptosis while overexpression of drug transporters MRP1, ABCG2 has been shown to mediate efflux of drugs from cancer cells, thus decreasing intracellular drug concentration leading to drug-resistance.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [1]

• Resistant Disease: Breast cancer bone metastasis [ICD-11: 2E03.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometric
• Mechanism Description: Interleukin-6 (IL-6), a pro-inflammatory cytokine produced in the tumor microenvironment by stromal cells, fibroblasts, and cancer cells. Binding of IL-6 to its receptor IL-6R on the cell membrane activates Janus Kinase 2 (JAK2) kinases. Activated JAK2 mediates phosphorylation, dimerization, and nuclear translocation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 signaling mediates the expression of various genes, including p53, Bcl-2, MRP1, and ABCG2. Bcl-2 and p53 are associated with regulation of apoptosis while overexpression of drug transporters MRP1, ABCG2 has been shown to mediate efflux of drugs from cancer cells, thus decreasing intracellular drug concentration leading to drug-resistance.

Preclinical Drug(s) 3 drug(s) in total

AZD1208/Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Sensitive Disease: Metastatic bone cancer [ICD-11: 2E03.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: AZD1208/Ruxolitinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: JAK2-V617F cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; Microarray gene expression analysis; Crystallization and structure determination assay
• Experiment for Drug Resistance: MTS assay; Colony formation assay

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Sensitive Disease: Metastatic bone cancer [ICD-11: 2E03.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: AZD1208/Ruxolitinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: JAK2-V617F cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; Microarray gene expression analysis; Crystallization and structure determination assay
• Experiment for Drug Resistance: MTS assay; Colony formation assay

CHZ868

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [3]

• Sensitive Disease: Metastatic bone cancer [ICD-11: 2E03.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: CHZ868
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: W515L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vivo Model: CD45.2 Jak2V617F mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell viability luminescent assay

Ruxolitinib/SGI-1776

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Sensitive Disease: Metastatic bone cancer [ICD-11: 2E03.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: Ruxolitinib/SGI-1776
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: JAK2-V617F cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; Microarray gene expression analysis; Crystallization and structure determination assay
• Experiment for Drug Resistance: MTS assay; Colony formation assay

References

• Ref 1: Bone interface modulates drug resistance in breast cancer bone metastasis .Colloids Surf B Biointerfaces. 2020 Nov;195:111224. doi: 10.1016/j.colsurfb.2020.111224. Epub 2020 Jun 26. 10.1016/j.colsurfb.2020.111224
• Ref 2: The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cellsOncotarget. 2015 Nov 24;6(37):40141-57. doi: 10.18632/oncotarget.5653.
• Ref 3: CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative NeoplasmsCancer Cell. 2015 Jul 13;28(1):15-28. doi: 10.1016/j.ccell.2015.06.006.