Disease Information

General Information of the Disease (ID: DIS00566)

• Name: Unspecified carcinoma of unspecified site
• ICD: ICD-11: 2D41

Type(s) of Resistant Mechanism of This Disease

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

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

Lapatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Cystine/glutamate transporter (SLC7A11) [1]

• Sensitive Disease: krasg12c inhibitor resistant tumors [ICD-11: 2D41]
• Sensitive Drug: Lapatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MiaPaCa-2 cells; Blood; Homo sapiens (Human); CVCL_0428
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu-1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vivo Model: BALB/c athymic nude mice model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Immunohistochemical assay; Xenograft mouse assay
• Mechanism Description: The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells.

Sorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Cystine/glutamate transporter (SLC7A11) [1]

• Sensitive Disease: krasg12c inhibitor resistant tumors [ICD-11: 2D41]
• Sensitive Drug: Sorafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MiaPaCa-2 cells; Blood; Homo sapiens (Human); CVCL_0428
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu-1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vivo Model: BALB/c athymic nude mice model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Immunohistochemical assay; Xenograft mouse assay
• Mechanism Description: The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells.

Sulfasalazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Cystine/glutamate transporter (SLC7A11) [1]

• Sensitive Disease: krasg12c inhibitor resistant tumors [ICD-11: 2D41]
• Sensitive Drug: Sulfasalazine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MiaPaCa-2 cells; Blood; Homo sapiens (Human); CVCL_0428
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu-1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vivo Model: BALB/c athymic nude mice model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Immunohistochemical assay; Xenograft mouse assay
• Mechanism Description: The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells.

References

• Ref 1: Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS(G12C) inhibitor resistant tumors. Redox Biol. 2024 Dec;78:103419.