Disease Information

General Information of the Disease (ID: DIS00101)

• Name: Thyroid cancer
• ICD: ICD-11: 2D10

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 15 drug(s) in total

Cabozantinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: Cabozantinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: MTC-TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the sensitivity of Cabozantinib by aberration of the drug's therapeutic target

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: Cabozantinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: MTC-TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.M918T (c.2753T>C) in gene RET cause the sensitivity of Cabozantinib by aberration of the drug's therapeutic target

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: Cabozantinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vivo Model: Female nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Kinase inhibition assay
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the sensitivity of Cabozantinib by unusual activation of pro-survival pathway

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [3]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: Cabozantinib
• Experimental Note: Identified from the Human Clinical Data

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-144 [4]

• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: ARO cells; Thyroid; Homo sapiens (Human); CVCL_0144
• In Vitro Model: HTori3 cell; Thyroid; Homo sapiens (Human); CVCL_4W02
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-144 could inhibit autophagy of ATC cells by down-regulating TGF-alpha, enhancing the cisplatin-sensitivity of ATC cells.

Key Molecule: Beclin-1 (BECN1) [5]

• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: hsa-mir-30d [5]

• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protransforming growth factor alpha (TGFA) [4]

• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: ARO cells; Thyroid; Homo sapiens (Human); CVCL_0144
• In Vitro Model: HTori3 cell; Thyroid; Homo sapiens (Human); CVCL_4W02
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-144 could inhibit autophagy of ATC cells by down-regulating TGF-alpha, enhancing the cisplatin-sensitivity of ATC cells.

Dabrafenib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [6]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 2-alpha (TOP2A) [7]

• Resistant Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.R450Q
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Regulation
• In Vitro Model: HTC-C3 cells; Pleural effusion; Homo sapiens (Human); CVCL_1295
• Experiment for Drug Resistance: Cell growth rate assay
• Mechanism Description: Several mutations have been identified in human topoisomerase IIalpha from cell lines which are resistant to anti-topoisomerase II agents. So far, three mutations at amino acids 439, 450 and 803 of DNA topoisomerase IIalpha have been reported in anticancer agent-resistant cell lines. It has been reported that introducing either of the mutations, Arg450Gln or Pro803Ser into the VM-1 cell line results in an enzyme that can confer drug resistance to yeast.

Key Molecule: DNA topoisomerase 2-alpha (TOP2A) [7]

• Resistant Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.P803S
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Regulation
• In Vitro Model: HTC-C3 cells; Pleural effusion; Homo sapiens (Human); CVCL_1295
• Experiment for Drug Resistance: Cell growth rate assay
• Mechanism Description: Several mutations have been identified in human topoisomerase IIalpha from cell lines which are resistant to anti-topoisomerase II agents. So far, three mutations at amino acids 439, 450 and 803 of DNA topoisomerase IIalpha have been reported in anticancer agent-resistant cell lines. It has been reported that introducing either of the mutations, Arg450Gln or Pro803Ser into the VM-1 cell line results in an enzyme that can confer drug resistance to yeast.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-27b-3p [8]

• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR27b-3p/PPARgamma signaling pathway; Regulation; hsa05206
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The inhibitor of miR-27b-3p can increase the Dox sensitivity of ATC Dox-resistant cells while over-expression of PPARGamma also increased the Dox sensitivity of ATC-resistant cells.

Key Molecule: Papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) [9]

• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: STAT3/INO80 signaling pathway; Inhibition; hsa04066
• In Vitro Model: FTC-133 cells; Thyroid; Homo sapiens (Human); CVCL_1219
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: FTC 238 cells; Thyroid; Homo sapiens (Human); CVCL_2447
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA PTCSC3 inhibits INO80 expression by negatively regulating STAT3, and thereby attenuating drug resistance of ATC to chemotherapy drug doxorubicin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Peroxisome proliferator-activated receptor gamma (PPARG) [8]

• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR27b-3p/PPARgamma signaling pathway; Regulation; hsa05206
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The inhibitor of miR-27b-3p can increase the Dox sensitivity of ATC Dox-resistant cells while over-expression of PPARGamma also increased the Dox sensitivity of ATC-resistant cells.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [9]

• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: STAT3/INO80 signaling pathway; Inhibition; hsa04066
• In Vitro Model: FTC-133 cells; Thyroid; Homo sapiens (Human); CVCL_1219
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: FTC 238 cells; Thyroid; Homo sapiens (Human); CVCL_2447
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA PTCSC3 inhibits INO80 expression by negatively regulating STAT3, and thereby attenuating drug resistance of ATC to chemotherapy drug doxorubicin.

Key Molecule: Papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) [9]

• Sensitive Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: STAT3/INO80 pathway; Regulation; hsa04550
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA PTCSC3 was low-expressed in ATC tissues and cells. Over-expressed PTCSC3 inhibited the drug resistance of ATC to doxorubicin. LncRNA PTCSC3 inhibits INO80 expression by negatively regulating STAT3, and thereby attenuating drug resistance of ATC to chemotherapy drug doxorubicin, providing novel strategies for improving efficiency of chemotherapy for ATC treatment.

Everolimus

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [10]

• Resistant Disease: Thyroid carcinoma [ICD-11: 2D10.4]
• Molecule Alteration: Missense mutation; p.F2108L
• Resistant Drug: Everolimus
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-genome sequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: On the basis of these findings, we hypothesized that mTORF2108L causes resistance to allosteric mTOR inhibition by preventing the binding of the drug to the protein.

Lenvatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [11]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: Lenvatinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: FTC-133 cells; Thyroid; Homo sapiens (Human); CVCL_1219
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: KHM-5M cells; Pleural effusion; Homo sapiens (Human); CVCL_2975
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: TCO-1 cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_3179
• In Vitro Model: RO82-W-1 cells; Thyroid; Homo sapiens (Human); CVCL_0582/CVCL_1663
• In Vitro Model: Nthy-ori 3-1 cells; N.A.; Homo sapiens (Human); CVCL_2659
• In Vitro Model: K1 cells; Thyroid; Homo sapiens (Human); CVCL_2537
• In Vitro Model: HTC-C3 cells; Pleural effusion; Homo sapiens (Human); CVCL_2273
• In Vitro Model: FTC-238 cells; Lung; Homo sapiens (Human); CVCL_2447
• In Vitro Model: FTC-236 cells; Cervical lymph node; Homo sapiens (Human); CVCL_2446
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; ICH assay
• Experiment for Drug Resistance: MSA assay; WST-8 assay

Levothyroxine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-206 [12]

• Sensitive Disease: Papillary thyroid carcinoma [ICD-11: 2D10.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Levothyroxine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: JNk signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: p38 signaling pathway; Inhibition; hsa04010
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: Nthy-ori3-1 cells; Thyroid; Homo sapiens (Human); CVCL_2659
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: Over-expression of miR-206 decreases the Euthyrox-resistance by targeting MAP4k3 in papillary thyroid carcinoma.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3) [12]

• Sensitive Disease: Papillary thyroid carcinoma [ICD-11: 2D10.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Levothyroxine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: JNk signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: p38 signaling pathway; Inhibition; hsa04010
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: Nthy-ori3-1 cells; Thyroid; Homo sapiens (Human); CVCL_2659
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: Over-expression of miR-206 decreases the Euthyrox-resistance by targeting MAP4k3 in papillary thyroid carcinoma.

Pralsetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [13]

• Resistant Disease: Advanced RET-altered thyroid cancer [ICD-11: 2D10.Y]
• Molecule Alteration: Mutation; .
• Resistant Drug: Pralsetinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: Cell-free DNAs (cfDNAs) analysis
• Mechanism Description: Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [14]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: Pralsetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: LC2/ad cells; Pleural effusion; Homo sapiens (Human); CVCL_1373
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [14]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: Pralsetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: LC2/ad cells; Pleural effusion; Homo sapiens (Human); CVCL_1373
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay

Pyrvinium

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Frizzled class receptor 7 (FZD7) [15]

• Sensitive Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Pyrvinium
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; ART sensitivity assay
• Experiment for Drug Resistance: CCK-8 cell proliferation assay; Flow cytometry
• Mechanism Description: Pyrvinium pamoate can overcome artemisinin's resistance in anaplastic thyroid cancer. The resistance of CAL-62 to ART was related to the upregulation of the WNT signaling pathway.

Key Molecule: Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) [15]

• Sensitive Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Pyrvinium
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; ART sensitivity assay
• Experiment for Drug Resistance: CCK-8 cell proliferation assay; Flow cytometry
• Mechanism Description: Pyrvinium pamoate can overcome artemisinin's resistance in anaplastic thyroid cancer. The resistance of CAL-62 to ART was related to the upregulation of the WNT signaling pathway.

Key Molecule: Sclerostin (SOST) [15]

• Sensitive Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Pyrvinium
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; ART sensitivity assay
• Experiment for Drug Resistance: CCK-8 cell proliferation assay; Flow cytometry
• Mechanism Description: Pyrvinium pamoate can overcome artemisinin's resistance in anaplastic thyroid cancer. The resistance of CAL-62 to ART was related to the upregulation of the WNT signaling pathway.

Key Molecule: Wnt family member 7B (WNT7B) [15]

• Sensitive Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Pyrvinium
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; ART sensitivity assay
• Experiment for Drug Resistance: CCK-8 cell proliferation assay; Flow cytometry
• Mechanism Description: Pyrvinium pamoate can overcome artemisinin's resistance in anaplastic thyroid cancer. The resistance of CAL-62 to ART was related to the upregulation of the WNT signaling pathway.

Regorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [16]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: Regorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HUVEC cells; Endothelium; Homo sapiens (Human); N.A.
• In Vitro Model: HAoSMC cells; N.A.; .; N.A.
• In Vivo Model: Female athymic NCr nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTitre-Glo assay
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the sensitivity of Regorafenib by unusual activation of pro-survival pathway

Selpercatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [13]

• Resistant Disease: Advanced RET-altered thyroid cancer [ICD-11: 2D10.Y]
• Molecule Alteration: Mutation; .
• Resistant Drug: Selpercatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: Cell-free DNAs (cfDNAs) analysis
• Mechanism Description: Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [17]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: Selpercatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vivo Model: mouse PDX model; Mus musculus
• Mechanism Description: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations.

Trametinib/Dabrafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [18]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Trametinib/Dabrafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Vandetanib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [19]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: Vandetanib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [19]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: Vandetanib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: PCR

Vemurafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [20]

• Resistant Disease: Papillary thyroid carcinoma [ICD-11: 2D10.1]
• Molecule Alteration: Missense mutation; p.V600E
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Low throughput experiment assay
• Mechanism Description: BRAFV600E is the most common mutation in PTC, occurring in about 60% of PTC tumors, and has been described as a clonal event since it occurs in the majority of tumor cells. BRAFV600E PTC exhibits primary resistance to RAI treatment, higher rates of tumor recurrence and metastases, and lower survival rates. Remarkably, the BRAFV600E mutation not only promotes thyroid tumor cell proliferation, adhesion, migration and invasion, but also up-regulates epigenetic pathways that silence expression of the sodium/iodide symporter. This blocks iodide uptake, which may be one cause of primary resistance to RAI. Present in other cancers, including 40-70% of malignant melanomas and 10% of colorectal cancers, BRAFV600E positive tumors provide one important case study for the evolution of drug resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Mitogen-activated protein kinase 3 (MAPK3) [21]

• Resistant Disease: Papillary thyroid carcinoma [ICD-11: 2D10.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: Alamar blue assay
• Mechanism Description: Resistance to vemurafenib in BCPAP appeared to be mediated by constitutive overexpression of phospho-ERK and by resistance to inhibition of both phospho-mTOR and phospho-S6 ribosomal protein after vemurafenib treatment.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [20]

• Resistant Disease: Papillary thyroid carcinoma [ICD-11: 2D10.1]
• Molecule Alteration: Structural variation; Copy number gain
• Resistant Drug: Vemurafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Low throughput experiment assay
• Mechanism Description: We found that MCL1 (myeloid cell leukemia 1, chromosome 1q) copy number gain is associated with resistance to vemurafenib treatment in metastatic BRAF V600E-PTC cells. MCL1, an anti-apoptotic member of the BCL2 family, is amplified in many cancers and plays a crucial role in tumor progression and metastasis, and likely in drug resistance.

YN-968D1

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box K2 (FOXK2) [22]

• Resistant Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: YN-968D1
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGFA/VEGFR1 signaling pathway; Activation; hsa05205
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vitro Model: SH-1-V2 cells; Esophagus; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: On VEGFR2 blockage by specific targeting agent, such as Apatinib, FOXK2 could rapidly trigger therapeutic resistance. Mechanical analyses revealed that VEGFA transcriptionally induced by FOXK2 could bind to VEGFR1 as a compensation for VEGFR2 blockage, which promoted angiogenesis by activating ERK, PI3K/AKT and P38/MAPK signaling in human umbilical vein endothelial cells (HUVECs). Synergic effect on anti-angiogenesis could be observed when VEGFR1 suppressor AF321 was included in VEGFR2 inhibition system, which clarified the pivot role of FOXK2 in VEGFR2 targeting therapy resistance.

Key Molecule: Vascular endothelial growth factor A (VEGFA) [22]

• Resistant Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: YN-968D1
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGFA/VEGFR1 signaling pathway; Activation; hsa05205
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vitro Model: SH-1-V2 cells; Esophagus; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: On VEGFR2 blockage by specific targeting agent, such as Apatinib, FOXK2 could rapidly trigger therapeutic resistance. Mechanical analyses revealed that VEGFA transcriptionally induced by FOXK2 could bind to VEGFR1 as a compensation for VEGFR2 blockage, which promoted angiogenesis by activating ERK, PI3K/AKT and P38/MAPK signaling in human umbilical vein endothelial cells (HUVECs). Synergic effect on anti-angiogenesis could be observed when VEGFR1 suppressor AF321 was included in VEGFR2 inhibition system, which clarified the pivot role of FOXK2 in VEGFR2 targeting therapy resistance.

Clinical Trial Drug(s) 5 drug(s) in total

Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [23]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vivo Model: Athymic nude mouse PDX xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay; Immunoprecipitation assy
• Experiment for Drug Resistance: SRB staining assay; Promega assay
• Mechanism Description: Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.

AZD1480

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [24]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: AZD1480
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: K1 cells; Thyroid; Homo sapiens (Human); CVCL_2537
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: The missense mutation p.M918T (c.2753T>C) in gene RET cause the sensitivity of AZD1480 by unusual activation of pro-survival pathway

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [24]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: AZD1480
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: K1 cells; Thyroid; Homo sapiens (Human); CVCL_2537
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the sensitivity of AZD1480 by unusual activation of pro-survival pathway

RO-5126766 free base

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [25]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: RO-5126766 free base
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210

Agerafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [26]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: Agerafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: LC-2/ad cells; Lung; Homo sapiens (Human); CVCL_1373
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Phospho-protein profiling assay
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A-RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of CCDC6-RET-rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in CCDC6-RET, NCOA4-RET, and KIF5B-RET-containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLC gamma.

Perifosine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [27]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Nonsense; p.R130* (c.388C>T)
• Sensitive Drug: Perifosine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The nonsense p.R130* (c.388C>T) in gene PTEN cause the sensitivity of Perifosine by unusual activation of pro-survival pathway.

Key Molecule: PI3-kinase alpha (PIK3CA) [27]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Sensitive Drug: Perifosine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of Perifosine by unusual activation of pro-survival pathway

Key Molecule: PI3-kinase alpha (PIK3CA) [27]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Drug: Perifosine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of Perifosine by unusual activation of pro-survival pathway

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

Motesanib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [28]

• Resistant Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Resistant Drug: Motesanib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Medullary thyroid cancer tissue; Pleural effusion; Homo sapiens (Human); CVCL_A656
• Mechanism Description: The missense mutation p.M918T (c.2753T>C) in gene RET cause the resistance of Motesanib by unusual activation of pro-survival pathway

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [28]

• Resistant Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Resistant Drug: Motesanib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Medullary thyroid cancer tissue; Pleural effusion; Homo sapiens (Human); CVCL_A656
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the resistance of Motesanib by unusual activation of pro-survival pathway

Preclinical Drug(s) 9 drug(s) in total

ALW-II-41-27

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [29]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: ALW-II-41-27
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/V804L cells; N.A.; Mus musculus (Mouse); CVCL_XZ25
• In Vitro Model: RET/S891A cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/L790F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/A883F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell counting assay

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [29]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: ALW-II-41-27
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/V804L cells; N.A.; Mus musculus (Mouse); CVCL_XZ25
• In Vitro Model: RET/S891A cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/L790F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/A883F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell counting assay

CLM3

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [30]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: CLM3
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vivo Model: Male CD nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Human cyclin D1 ELISA assay
• Experiment for Drug Resistance: WST-1 assay; Cell counting assay; Hoechst uptake assay; Annexin V binding assay

Dasatinib/SCH772984

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [23]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Dasatinib/SCH772984
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vivo Model: Athymic nude mouse PDX xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay; Immunoprecipitation assy
• Experiment for Drug Resistance: SRB staining assay; Promega assay
• Mechanism Description: Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.

Dasatinib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [23]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Dasatinib/Trametinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vivo Model: Athymic nude mouse PDX xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay; Immunoprecipitation assy
• Experiment for Drug Resistance: SRB staining assay; Promega assay
• Mechanism Description: Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.

HG-6-63-01

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [29]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: HG-6-63-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/V804L cells; N.A.; Mus musculus (Mouse); CVCL_XZ25
• In Vitro Model: RET/S891A cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/L790F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/A883F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell counting assay

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [29]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: HG-6-63-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/V804L cells; N.A.; Mus musculus (Mouse); CVCL_XZ25
• In Vitro Model: RET/S891A cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/L790F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/A883F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell counting assay

MK2206

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [31]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Nonsense; p.R130* (c.388C>T)
• Sensitive Drug: MK2206
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The nonsense p.R130* (c.388C>T) in gene PTEN cause the sensitivity of MK2206 by unusual activation of pro-survival pathway.

Key Molecule: GTPase Hras (HRAS) [31]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.G13R (c.37G>C)
• Sensitive Drug: MK2206
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.G13R (c.37G>C) in gene HRAS cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [31]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.Q61R (c.182A>G)
• Sensitive Drug: MK2206
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Key Molecule: PI3-kinase alpha (PIK3CA) [31]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Drug: MK2206
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

MK2206/Temsirolimus

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [31]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Drug: MK2206/Temsirolimus
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of MK2206 + Temsirolimus by unusual activation of pro-survival pathway

Key Molecule: PI3-kinase alpha (PIK3CA) [31]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Sensitive Drug: MK2206/Temsirolimus
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: Hth74 cells; Thyroid gland; Homo sapiens (Human); CVCL_6288
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of MK2206 + Temsirolimus by unusual activation of pro-survival pathway

TAK-632

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [32]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: TAK-632
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of TAK-632 by aberration of the drug's therapeutic target

XMD15-44

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [29]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Drug: XMD15-44
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/V804L cells; N.A.; Mus musculus (Mouse); CVCL_XZ25
• In Vitro Model: RET/S891A cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/L790F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/A883F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell counting assay

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [29]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Drug: XMD15-44
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/V804L cells; N.A.; Mus musculus (Mouse); CVCL_XZ25
• In Vitro Model: RET/S891A cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/M918T cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/L790F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/C634R cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: RET/A883F cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: RET/V804M cells; Bone marrow; Mus musculus (Mouse); CVCL_XZ26
• In Vitro Model: RET/E768D cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell counting assay

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

Iodine-131

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Solute carrier family 6 member 9 (SLC6A9) [33]

• Resistant Disease: Papillary thyroid carcinoma [ICD-11: 2D10.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Iodine-131
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: SLC6A9/PARP1 signaling pathway; Inhibition; hsa04064
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: SLC6A9-5:2 overexpression was positively correlated with PARP-1 mRNA and protein levels, which restored the sensitivity of resistant thyroid cancer cells. SLC6A9 is positively correlated with PARP-1 expression, and PARP-1 inhibition makes thyroid cancer cells resistant to 131I. Upregulation of the SLC6A9-PARP-1 pathway enhanced the sensitivity to 131I treatment through energy exhaustion during excess RNA repair.

Key Molecule: hsa-mir-182 [34]

• Resistant Disease: Thyroid carcinoma [ICD-11: 2D10.4]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Iodine-131
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: FTC-133 cells; Thyroid; Homo sapiens (Human); CVCL_1219
• Experiment for Molecule Alteration: qRT-PCR; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: MEG3 expression was decreased while miR-182 expression was increased in 131I-resistant TC cells.

Key Molecule: Maternally expressed 3 (MEG3) [34]

• Resistant Disease: Thyroid carcinoma [ICD-11: 2D10.4]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Iodine-131
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: FTC-133 cells; Thyroid; Homo sapiens (Human); CVCL_1219
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: MEG3 expression was decreased while miR-182 expression was increased in 131I-resistant TC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [33]

• Resistant Disease: Papillary thyroid carcinoma [ICD-11: 2D10.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Iodine-131
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: SLC6A9/PARP1 signaling pathway; Inhibition; hsa04064
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: SLC6A9-5:2 overexpression was positively correlated with PARP-1 mRNA and protein levels, which restored the sensitivity of resistant thyroid cancer cells. SLC6A9 is positively correlated with PARP-1 expression, and PARP-1 inhibition makes thyroid cancer cells resistant to 131I. Upregulation of the SLC6A9-PARP-1 pathway enhanced the sensitivity to 131I treatment through energy exhaustion during excess RNA repair.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [20]

• Resistant Disease: Thyroid carcinoma [ICD-11: 2D10.4]
• Molecule Alteration: Missense mutation; p.V600E
• Resistant Drug: Iodine-131
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Epigenetic signaling pathway; Activation; hsa05207
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Low throughput experiment assay
• Mechanism Description: Primary resistance appears to develop early in tumorigenesis via genetic or epigenetic events that activate pro-proliferation pathways or inhibit pathways that stimulate cell death. Loss or gain of a cell surface receptor or transporter or other alterations in the drug target pathway can also lead to resistance against pharmacological agents, as described below for PTC with the BRAFV600E mutation. BRA FV600E PTC exhibits primary resistance to RAI treatment, higher rates of tumor recurrence and metastases, and lower survival rates. Remarkably, the BRAFV600E mutation not only promotes thyroid tumor cell proliferation, adhesion, migration and invasion, but also up-regulates epigenetic pathways that silence expression of the sodium/iodide symporter. This blocks iodide uptake, which may be one cause of primary resistance to RAI. BRAF V600E PTC exhibits primary resistance to RAI treatment, higher rates of tumor recurrence and metastases, and lower survival rates.

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