Drug Information

Drug (ID: DG00651) and It's Reported Resistant Information

• Name: Bevacizumab
• Indication:
  In total 7 Indication(s)
  Brain metastases [ICD-11: 2D50-2E2Z]; Approved; [1]
  Colorectal cancer [ICD-11: 2B91]; Approved; [1]
  Lung cancer [ICD-11: 2C25]; Approved; [1]
  Metastatic colorectal cancer [ICD-11: 2D85]; Approved; [1]
  Metastatic colorectal cancer [ICD-11: 2D85]; Approved; [1]
  Ovarian cancer [ICD-11: 2C73]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Retinal disorders [ICD-11: 9B78]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Colorectal cancer [ICD-11: 2B91]; [3]
  Ovarian cancer [ICD-11: 2C73]; [1]
• Target: Vascular endothelial growth factor A (VEGFA); VEGFA_HUMAN; [1]
• TTD Drug ID: D04KBL

Type(s) of Resistant Mechanism of This Drug

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Ovarian cancer [ICD-11: 2C73]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: EPH receptor B4 (EPHB4) [1]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.42E-09; Fold-change: 2.17E-01; Z-score: 6.07E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Primary pulmonary lymphoepithelioma-like carcinoma tissue; N.A.
• In Vivo Model: Athymic BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: EphB4 was overexpressed in BV-resistant xenograft models instead of other common receptor tyrosine kinases. In addition, when coadministrated with EphB4 blocker NVP-BHG712, the antitumor effect of BV was significantly enhanced in the resistant model, further confirmed the role of EphB4 in BV-resistant ovarian cancer. These results indicate that NVP-BHG712 reverses EphB4 overexpression-mediated resistance to BV.

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [4]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.93 Å; PDB: 5GIR
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.20 Å; PDB: 6IO0

RMSD: 1.64; TM score: 0.30204; Amino acid change: R132C

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; N.A.
• Mechanism Description: The missense mutation p.R132C (c.394C>T) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [4]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132S (c.394C>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; N.A.
• Mechanism Description: The missense mutation p.R132S (c.394C>A) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [4]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132L (c.395G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; N.A.
• Mechanism Description: The missense mutation p.R132L (c.395G>T) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Histone H3 [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.

Key Molecule: Enolase 2 (ENO2) [5]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vivo Model: 6-to 8-week-old female NOD/SCID mice, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Here, we found that high levels of ENO2 expression and ENO2-related neuroendocrine differentiation were associated with resistance to antiangiogenic therapy in CRC. Notably, the ENO2-derived PEP was responsible for ENO2-mediated resistance to antiangiogenic therapy in CRC, and PEP enhanced beta-catenin Lys49 acetylation by selectively inhibiting histone deacetylase 1 (HDAC1) activity.

Key Molecule: Enolase 2 (ENO2) [5]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: 4-to 6-week-old female BALB/c nude mice, with HCT116vector, HCT116ENO2, HCT116shNC and HCT116shENO2, Rego-resistant SW620 or Bev-resistant HCT116 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Here, we found that high levels of ENO2 expression and ENO2-related neuroendocrine differentiation were associated with resistance to antiangiogenic therapy in CRC. Notably, the ENO2-derived PEP was responsible for ENO2-mediated resistance to antiangiogenic therapy in CRC, and PEP enhanced beta-catenin Lys49 acetylation by selectively inhibiting histone deacetylase 1 (HDAC1) activity.

Key Molecule: Histone H3 [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Patient-derived xenograft (PDX) mice; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Quantification viability of patient-derived organoids
• Mechanism Description: Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.

Key Molecule: Histone H3 [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Patient-derived xenograft (PDX) mice; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.

Key Molecule: Histone H3 [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Western blot assay
• Mechanism Description: Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.

References

• Ref 1: Resistance to bevacizumab in ovarian cancer SKOV3 xenograft due to EphB4 overexpression .J Cancer Res Ther. 2019 Oct-Dec;15(6):1282-1287. doi: 10.4103/0973-1482.204896. 10.4103/0973-1482.204896
• Ref 2: Anti-VEGF-refractory exudative age-related macular degeneration: differential response according to features on optical coherence tomography .Korean J Ophthalmol. 2013 Dec;27(6):425-32. doi: 10.3341/kjo.2013.27.6.425. Epub 2013 Nov 15. 10.3341/kjo.2013.27.6.425
• Ref 3: Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer. Autophagy. 2024 Jan;20(1):114-130.
• Ref 4: Correlation between IDH1 gene mutation status and survival of patients treated for recurrent gliomaAnticancer Res. 2011 Dec;31(12):4457-63.
• Ref 5: ENO2-derived phosphoenolpyruvate functions as an endogenous inhibitor of HDAC1 and confers resistance to antiangiogenic therapy. Nat Metab. 2023 Oct;5(10):1765-1786.