Disease Information

General Information of the Disease (ID: DIS00504)

• Name: Liver cancer
• ICD: ICD-11: 2C12

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [1]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Cisplatin
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Erlotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [1]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Sensitive Drug: Erlotinib
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [1]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Fluorouracil
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [1]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Gemcitabine
• Molecule Alteration: phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [1]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Gemcitabine
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: L-type amino acid transporter 2 (LAT2) [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KKU-213B cells; Liver; Homo sapiens (Human); CVCL_M264
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway.

Curcumin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: L-type amino acid transporter 2 (LAT2) [2]

• Metabolic Type: Glutamine metabolism
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Sensitive Drug: Curcumin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KKU-213B cells; Liver; Homo sapiens (Human); CVCL_M264
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway.

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

Erlotinib/Gemcitabine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [1]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Sensitive Drug: Erlotinib/Gemcitabine
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

References

• Ref 1: Targeting EGFR Activation to Overcome Gemcitabine Resistance in Cholangiocarcinoma. Anticancer Res. 2024 Dec;44(12):5393-5404.
• Ref 2: Curcumin synergistically enhances the efficacy of gemcitabine against gemcitabine-resistant cholangiocarcinoma via the targeting LAT2/glutamine pathway. Sci Rep. 2024 Jul 11;14(1):16059.