Disease Information

General Information of the Disease (ID: DIS00508)

• Name: Brain cancer
• ICD: ICD-11: 2A00

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Clinical Trial Drug(s) 2 drug(s) in total

BAY2402234

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Dihydroorotate dehydrogenase (DHODH) [1]

• Metabolic Type: Nucleic acid metabolism
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: BAY2402234
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.05E-05; Fold-change: 3.01E-01; Z-score: 4.81E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Recently, the dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 displayed efficacy in different brain cancer animal models

Alisertib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Aurora kinase A (AURKA) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Alisertib
• Molecule Alteration: Autophosphorylation; Thr288
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: GBM22 PDX cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: SF188 PDX cells; Brain; Homo sapiens (Human); CVCL_6948
• In Vitro Model: Silenced PGC1alpha in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: Silenced PGC1alpha in SF188 cells; Brain; Homo sapiens (Human); CVCL_6948
• In Vitro Model: Transfect T58A mutant c-Myc in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: Transfected c-Myc in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The response to Aurora kinase A inhibitors depends on glycolysis and that tumor cells with an oxidative metabolic phenotype will be more resistant to Aurora kinase A inhibitor treatment. Moreover, in a manner dependent on the transcription factors c-MYC and PGC1alpha treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo.

Key Molecule: Aurora kinase A (AURKA) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Alisertib
• Molecule Alteration: Autophosphorylation; Thr288
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: GBM22 orthotopic PDX model; orthotopic murine GBM model; subcutis of immunocompromised Nu/Nu mice, GBM12 cells; subcutis of immunocompromised Nu/Nu mice, GBM43 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: The response to Aurora kinase A inhibitors depends on glycolysis and that tumor cells with an oxidative metabolic phenotype will be more resistant to Aurora kinase A inhibitor treatment. Moreover, in a manner dependent on the transcription factors c-MYC and PGC1alpha treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo.

Approved Drug(s) 4 drug(s) in total

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate carboxylase (PC) [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models.

Pimozide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Sterol regulatory element-binding protein 1 (SREBP-1) [4]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Pimozide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: LC-MS
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo.

Key Molecule: Alanine-serine-cysteine transporter 2 (ASCT2) [4]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Pimozide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: LC-MS
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo.

Temozolomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Activating transcription factor 4 (ATF4) [5]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Temozolomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNT-22 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.

Key Molecule: Histone H3 [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Temozolomide
• Molecule Alteration: Lactylation; H3K9la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TBD0220TR cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Lactylation is upregulated in recurrent glioblastoma (GBM) tissues and temozolomide (TMZ)-resistant cells, mainly concentrated in histone H3K9. H3K9 lactylation activates LUC7L2 transcription. LUC7L2 mediates MLH1 intron 7 retention to reduce MLH1 expression, thereby inhibit mismatch repair (MMR), ultimately leading to TMZ resistance.

Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CREB-regulated transcription coactivator 1 (CRTC1) [7]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: Trametinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: TORC1 signaling pathway; Regulation; N.A.
• In Vitro Model: BT-40 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: NCH-MN-1 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: IC-3635 cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: C.B.17SC scid?/? mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Clonogenic assay; Cellular viability assay; In vivo tumor growth inhibition assay; Orthotopic xenograft assay
• Mechanism Description: In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance.

References

• Ref 1: Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment. Metabolites. 2024 Jul 27;14(8):413.
• Ref 2: Guggulsterone from Commiphora mukul potentiates anti-glioblastoma efficacy of temozolomide in vitro and in vivo via down-regulating EGFR/PI3K/Akt signaling and NF-kappaB activation. J Ethnopharmacol. 2023 Jan 30;301:115855.
• Ref 3: Metabolic profiling of glioblastoma stem cells reveals pyruvate carboxylase as a critical survival factor and potential therapeutic target. Neuro Oncol. 2024 Sep 5;26(9):1572-1586.
• Ref 4: Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma. Cell Rep Med. 2024 Sep 17;5(9):101706.
• Ref 5: Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide. Sci Rep. 2021 Jul 8;11(1):14161.
• Ref 6: Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2-Mediated MLH1 Intron Retention. Adv Sci (Weinh). 2024 May;11(19):e2309290.
• Ref 7: Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models. Clin Cancer Res. 2022 Sep 1;28(17):3836-3849.
• Ref 8: Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma. Nat Commun. 2021 Sep 1;12(1):5203.