Disease Information

General Information of the Disease (ID: DIS00513)

• Name: Lung cancer
• ICD: ICD-11: 2C25

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

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

Pemetrexed

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Family with sequence similarity 83 member B (FAM83B) [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Pemetrexed
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.89E-39; Fold-change: 1.68E+00; Z-score: 1.75E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The mechanistic analysis demonstrated that FAM83B impedes the translocation of calbindin 2 (CALB2) from the cytoplasm to the mitochondria, resulting in the inhibition of apoptosis and the promotion of mitochondrial activity. Consequently, this ultimately confers resistance to chemotherapy in LUAD. Furthermore, the administration of metformin, which blocks mitochondrial oxidative phosphorylation (OXPHOS), can restore sensitivity to drug resistance in LUAD. Taken together, these findings provide substantial evidence supporting the notion that FAM83B enhances chemotherapy resistance in LUAD through the upregulation of mitochondrial metabolism and the inhibition of apoptosis.

Osimertinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Family with sequence similarity 83 member B (FAM83B) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.89E-39; Fold-change: 1.68E+00; Z-score: 1.75E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: PI/Annexin V apoptosis assay
• Mechanism Description: Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA9-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Key Molecule: Family with sequence similarity 83 member B (FAM83B) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.89E-39; Fold-change: 1.68E+00; Z-score: 1.75E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: PI/Annexin V apoptosis assay
• Mechanism Description: Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA8-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Key Molecule: Family with sequence similarity 83 member B (FAM83B) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.89E-39; Fold-change: 1.68E+00; Z-score: 1.75E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: PI/Annexin V apoptosis assay
• Mechanism Description: Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA7-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Key Molecule: Family with sequence similarity 83 member B (FAM83B) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.89E-39; Fold-change: 1.68E+00; Z-score: 1.75E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: PI/Annexin V apoptosis assay
• Mechanism Description: Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA6-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Key Molecule: Family with sequence similarity 83 member B (FAM83B) [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.89E-39; Fold-change: 1.68E+00; Z-score: 1.75E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: PI/Annexin V apoptosis assay
• Mechanism Description: Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA5-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [3]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT1 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [3]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT2 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [3]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT3 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [3]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_B0JT
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT4 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [3]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Male nude mice; Mice
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT5 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

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

CMU-0101

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein kinase C delta type (PRKCD) [4]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: CMU-0101
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The sotrastaurin derivative CMU-0101 exhibited an elevated affinity for binding to the ATP-binding site of PKCdelta and effectively suppressed nuclear PKCdelta in resistant cells in comparison to sotrastaurin. Protein kinase C (PKC) is a family of serine/threonine kinases that play important roles in signal transduction, cell proliferation, differentiation, and apoptosis. In lung cancers, the nuclear localization of PKC delta (nPKCdelta) has emerged as a common resistant mediator across various known TKI-resistant pathways. nPKCdelta is actively expressed in a significant portion of TKI-resistant patients and is associated with poor survival in EGFR-mutant patients treated with TKIs. The nPKCdelta-mediated pathway, including AKT and NF-kB, has been implicated in promoting resistance to EGFR inhibitors by activating alternative survival signaling pathways that bypass the blocked EGFR signaling and bolster tumor growth.

References

• Ref 1: FAM83B regulates mitochondrial metabolism and anti-apoptotic activity in pulmonary adenocarcinoma. Apoptosis. 2024 Jun;29(5-6):743-756.
• Ref 2: Ferritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Nat Commun. 2024 May 17;15(1):4195.
• Ref 3: HIF-1alpha-HPRT1 axis promotes tumorigenesis and gefitinib resistance by enhancing purine metabolism in EGFR-mutant lung adenocarcinoma. J Exp Clin Cancer Res. 2024 Sep 30;43(1):269.
• Ref 4: Development of triazole-based PKC-inhibitors to overcome resistance to EGFR inhibitors in EGFR-mutant lung cancers. Am J Cancer Res. 2023 Oct 15;13(10):4693-4707. eCollection 2023.