Disease Information

General Information of the Disease (ID: DIS00052)

• Name: Acute myeloid leukemia
• ICD: ICD-11: 2A60

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 25 drug(s) in total

Arsenic trioxide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-204 [1]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Arsenic trioxide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cancer progression; Inhibition; hsa05200
• In Vitro Model: AML-5 cells; Peripheral blood; Homo sapiens (Human); CVCL_1620
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 6 (BIRC6) [1]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Arsenic trioxide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BIRC6/p53-mediated apoptosis signaling pathway; Activation; hsa04210
• In Vitro Model: AML-5 cells; Peripheral blood; Homo sapiens (Human); CVCL_1620
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis.

Avapritinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [2]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• Sensitive Drug: Avapritinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: M-07e cells; Peripheral blood; Homo sapiens (Human); CVCL_2106
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: Chinese hamster ovary (CHO)-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Enzyme-linked immunosorbent assay; Cellular proliferation test assay

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-335 [3]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Nodal/TFG-alpha signaling pathway; Regulation; hsa04350
• Cell Pathway Regulation: Wnt/alpha -catenin signaling pathway; Regulation; hsa04310
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Relapse-free survival and overall survival assay
• Mechanism Description: The expression levels of miR-335 in bone marrow and serum samples from adult patients with AML (except M3) were significantly associated with the Ara-C-based chemotherapy response and clinical outcome after treatment.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-126-5p [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKTsignaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Transfection of the mimic miR-126-5p into the AML cell line, kG-1, resulted in a decrease in the sensitivity to cytarabin and the expression level of klotho mRNA as well as the elevation in the phosphorylation of Akt. The results of the present study demonstrated that higher expression levels of miR-126-5p/3p in patients with AML resulted in a poorer prognosis. Furthermore, miR-126-5p elevated the phosphorylation of Akt.

Key Molecule: hsa-mir-181 [5]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.

Key Molecule: hsa-let-7a [6]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vitro Model: Molm13 cells; Blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: OCI-AML3 cells; Blood; Homo sapiens (Human); CVCL_1844
• In Vivo Model: AML nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Xenografts of primary human AML cells engineered to overexpress let-7a exhibited enhanced sensitivity to cytarabine.

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [7]

• Sensitive Disease: Myeloid leukemia [ICD-11: 2A60.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: One of the predicted targets of miR-32 lies in the 3' untranslated region (UTR) of BCL2L11 gene, which encodes the pro-apoptotic protein Bim, miR-32 blockade is sufficient to elevate Bim expression and sensitize AML cells to chemotherapy-induced apoptosis.

Key Molecule: hsa-mir-32 [7]

• Sensitive Disease: Myeloid leukemia [ICD-11: 2A60.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: One of the predicted targets of miR-32 lies in the 3' untranslated region (UTR) of BCL2L11 gene, which encodes the pro-apoptotic protein Bim, miR-32 blockade is sufficient to elevate Bim expression and sensitize AML cells to chemotherapy-induced apoptosis.

Key Molecule: hsa-mir-21 [8]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: AMO-miR-21 significantly sensitizes HL60 cells to Ara-C byinducing apoptosis and these effects of AMO-miR-21 may be partially due to its up-regulation ofPDCD4.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Klotho (KL) [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKTsignaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Transfection of the mimic miR-126-5p into the AML cell line, kG-1, resulted in a decrease in the sensitivity to cytarabin and the expression level of klotho mRNA as well as the elevation in the phosphorylation of Akt. The results of the present study demonstrated that higher expression levels of miR-126-5p/3p in patients with AML resulted in a poorer prognosis. Furthermore, miR-126-5p elevated the phosphorylation of Akt.

Key Molecule: High mobility group protein B1 (HMGB1) [5]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [5]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.

Key Molecule: Programmed cell death protein 4 (PDCD4) [8]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: AMO-miR-21 significantly sensitizes HL60 cells to Ara-C byinducing apoptosis and these effects of AMO-miR-21 may be partially due to its up-regulation ofPDCD4.

Daunorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [9]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R882H
• Resistant Drug: Daunorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ADAM9/EGFR signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: DNMT3A mutations are most common in AML. DNMT3A mutant AML has been linked to anthracycline resistance and poor prognosis in some studies. Many of these mutations occur in genes with established roles in the regulation and maintenance of DNA methylation and/or chromatin modifications in hematopoietic stem/progenitor cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-33b [10]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Daunorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: MCL-1 participates in the regulation of DNR sensitivity mediated by miR-33b and overexpression of miR-33b enhances DNR sensitivity by downregulating MCL-1 in AML cells.

Key Molecule: hsa-mir-9 [11]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Daunorubicin
• 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
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: miR-9 improved the anti-tumor effects of Dnr by inhibiting myeloid cell leukemia-1 (MCL-1) expression, which was dependent on downregulation of EIF5A2 expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [10]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Daunorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: MCL-1 participates in the regulation of DNR sensitivity mediated by miR-33b and overexpression of miR-33b enhances DNR sensitivity by downregulating MCL-1 in AML cells.

Key Molecule: Eukaryotic translation initiation factor 5A-2 (EIF5A2) [10]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Daunorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-33b regulates sensitivity to daunorubicin in acute myelocytic leukemia by regulating eukaryotic translation initiation factor 5A-2.

Key Molecule: Eukaryotic translation initiation factor 5A-2 (EIF5A2) [11]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Daunorubicin
• 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
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: miR-9 improved the anti-tumor effects of Dnr by inhibiting myeloid cell leukemia-1 (MCL-1) expression, which was dependent on downregulation of EIF5A2 expression.

Dexamethasone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: CREB-binding protein (CREBBP) [12], [13]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [14]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: HS-5 cells; Bone marrow; Homo sapiens (Human); CVCL_3720
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 epigenetically suppressed miR-34a expression by recruiting EZH2 to the promoter region of miR-34a and increasing H3k27me3 level to confer adriamycin resistance in acute myeloid leukemia.

Key Molecule: Taurine up-regulated 1 (TUG1) [14]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: HS-5 cells; Bone marrow; Homo sapiens (Human); CVCL_3720
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 epigenetically suppressed miR-34a expression by recruiting EZH2 to the promoter region of miR-34a and increasing H3k27me3 level to confer adriamycin resistance in acute myeloid leukemia.

Key Molecule: hsa-miR-520c-3p [15]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• 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: miR520c-3p/S100A4 signaling pathway; Regulation; hsa05206
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: HOXA-AS2 Can enhance S100A4 expression by suppressing miR-520c-3p expression to promote adriamycin resistance in acute myeloid leukemia through the miR-520c-3p /S100A4 pathway.

Key Molecule: HOXA cluster antisense RNA 2 (HOXA-AS2) [15]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• 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: miR520c-3p/S100A4 signaling pathway; Regulation; hsa05206
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: HOXA-AS2 Can enhance S100A4 expression by suppressing miR-520c-3p expression to promote adriamycin resistance in acute myeloid leukemia through the miR-520c-3p /S100A4 pathway.

Key Molecule: hsa-miR-153-5p [16]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.

Key Molecule: hsa-miR-183-5p [16]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.

Key Molecule: Long non-protein coding RNA 239 (LINC00239) [17]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: Long non coding RNA linc00239 promotes malignant behaviors and chemoresistance against doxorubicin partially via activation of the PI3k/Akt/mTOR pathway in acute myeloid leukaemia cells.

Key Molecule: Urothelial cancer associated 1 (UCA1) [18]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR125a/hexokinase 2 pathway; Regulation; hsa05206
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hk2, a target of miR-125a, was positively regulated by uca1 in HL60, and HL60/ADR cells,and UCA1 overexpression significantly attenuated miR-125-mediated inhibition on HIF-1alpha-dependent glycolysis in HL60 and HL60/ADR cells.

Key Molecule: hsa-mir-125b [19]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-125b could promote leukemic cell proliferation and inhibit cell apoptosis by regulating the expression of tumor suppressor BCL2-antagonist/killer 1 (Bak1). transfection of a miR-125b duplex into AML cells can increase their resistance to therapeutic drugs.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein S100-A4 (S100A4) [15]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• 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: miR520c-3p/S100A4 signaling pathway; Regulation; hsa05206
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: HOXA-AS2 Can enhance S100A4 expression by suppressing miR-520c-3p expression to promote adriamycin resistance in acute myeloid leukemia through the miR-520c-3p /S100A4 pathway.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [16]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.

Key Molecule: RAC serine/threonine-protein kinase (AKT) [17]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: Long non coding RNA linc00239 promotes malignant behaviors and chemoresistance against doxorubicin partially via activation of the PI3k/Akt/mTOR pathway in acute myeloid leukaemia cells.

Key Molecule: Hexokinase-2 (HK2) [18]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR125a/hexokinase 2 pathway; Regulation; hsa05206
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hk2, a target of miR-125a, was positively regulated by uca1 in HL60, and HL60/ADR cells,and UCA1 overexpression significantly attenuated miR-125-mediated inhibition on HIF-1alpha-dependent glycolysis in HL60 and HL60/ADR cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa_circ_PAN3 [16]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.

Key Molecule: hsa-miR-153-5p [16]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.

Key Molecule: hsa-miR-183-5p [16]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.

Key Molecule: hsa-mir-217 [20]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: microRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting kRAS.

Key Molecule: Urothelial cancer associated 1 (UCA1) [18]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• 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: miR125a/hexokinase 2 pathway; Regulation; hsa05206
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hk2, a target of miR-125a, was positively regulated by uca1 in HL60, and HL60/ADR cells,and UCA1 overexpression significantly attenuated miR-125-mediated inhibition on HIF-1alpha-dependent glycolysis in HL60 and HL60/ADR cells.

Key Molecule: hsa-mir-181 [5]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase KRas (KRAS) [20]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: microRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting kRAS.

Key Molecule: Hexokinase-2 (HK2) [18]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• 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: miR125a/hexokinase 2 pathway; Regulation; hsa05206
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hk2, a target of miR-125a, was positively regulated by uca1 in HL60, and HL60/ADR cells,and UCA1 overexpression significantly attenuated miR-125-mediated inhibition on HIF-1alpha-dependent glycolysis in HL60 and HL60/ADR cells.

Key Molecule: High mobility group protein B1 (HMGB1) [5]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [5]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.

Gemtuzumab ozogamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myeloid cell surface antigen CD33 (CD33) [21]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Gemtuzumab ozogamicin
• 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: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: GDM-1 cells; Blood; Homo sapiens (Human); CVCL_1230
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• In Vitro Model: TF-1 cells; Blood; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: Western Blot Analysis
• Experiment for Drug Resistance: Flow cytometric SCNP assays
• Mechanism Description: AKT signaling modulates GO/calicheamicin-gamma1 cytotoxicity and is associated with cellular-resistance to these drugs. In turn, inhibition of AKT activation can greatly increase GO/calicheamicin-gamma1 sensitivity.

Gilteritinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [22]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Sensitive Drug: Gilteritinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Idarubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [23]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R882H (c.2645G>A)
• Sensitive Drug: Idarubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• In Vivo Model: NOD/SCID mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.R882H (c.2645G>A) in gene DNMT3A cause the sensitivity of Idarubicin by unusual activation of pro-survival pathway

Ivosidenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [24]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Sensitive Drug: Ivosidenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [24]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132S (c.394C>A)
• Sensitive Drug: Ivosidenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [24]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132G (c.394C>G)
• Sensitive Drug: Ivosidenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [24]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: Ivosidenib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [24]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132L (c.395G>T)
• Sensitive Drug: Ivosidenib
• Experimental Note: Identified from the Human Clinical Data

Ketorolac

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa_circ_0001946 [25]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Ketorolac
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Efflux pump genes expression analysis
• Mechanism Description: Ketorolac-fluconazole in vitro combination would be a promising strategy for further clinical in vivo trials to overcome fluconazole resistance in AML patients on induction chemotherapy. To our knowledge, the current study is the first in vitro report on the use of ketorolac in reverting fluconazole resistance in C. albicans isolated from AML patients. Resistance of C. albicans to azole antifungals is associated with overexpression of efflux pump genes especially CDR1 and MDR1.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [25]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Ketorolac
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Efflux pump genes expression analysis
• Mechanism Description: Ketorolac-fluconazole in vitro combination would be a promising strategy for further clinical in vivo trials to overcome fluconazole resistance in AML patients on induction chemotherapy. To our knowledge, the current study is the first in vitro report on the use of ketorolac in reverting fluconazole resistance in C. albicans isolated from AML patients. Resistance of C. albicans to azole antifungals is associated with overexpression of efflux pump genes especially CDR1 and MDR1.

Lestaurtinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [26]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835E
• Resistant Drug: Lestaurtinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Mechanism Description: Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [26]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Chromosome variation; FLT3/ITD (Internal tandem duplication )
• Resistant Drug: Lestaurtinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Mechanism Description: Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.

Mercaptopurine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [13], [27]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R238W (c.c712t)
• Resistant Drug: Mercaptopurine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [13], [27]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.S445F (c.c1334t)
• Resistant Drug: Mercaptopurine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).

Midostaurin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ras-related C3 botulinum toxin substrate 1 (RAC1) [28]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Function; Activation
• Resistant Drug: Midostaurin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: RAC1 activation assay
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; Flow cytometric analysis
• Mechanism Description: Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [29]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.Y842C (c.2525A>G)
• Sensitive Drug: Midostaurin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.Y842C (c.2525A>G) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [30]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Sensitive Drug: Midostaurin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Mechanism Description: The missense mutation p.D835Y (c.2503G>T) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [31]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• Sensitive Drug: Midostaurin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [22]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Sensitive Drug: Midostaurin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Mitoxantrone

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-494 [32]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Mitoxantrone
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-494 activation suppresses bone marrow stromal cell-mediated drug resistance in acute myeloid leukemia cells.

Pexidartinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y
• Resistant Drug: Pexidartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835Y mutation was 206, the pexidartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835V
• Resistant Drug: Pexidartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835V mutation was 320, the pexidartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835I
• Resistant Drug: Pexidartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835I mutation was 1937, the pexidartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835F
• Resistant Drug: Pexidartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835F mutation was 415, the pexidartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Frameshift mutation; p.D835Del
• Resistant Drug: Pexidartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835Del mutation was 121, the pexidartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691L
• Resistant Drug: Pexidartinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691L
• Resistant Drug: Pexidartinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691L
• Resistant Drug: Pexidartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Mechanism Description: The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation+Internal tandem duplication mutation; p.F691L+ FLT3-ITD
• Sensitive Drug: Pexidartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Mechanism Description: The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations.

Regorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [31]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• Sensitive Drug: Regorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Ripretinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [31]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• Sensitive Drug: Ripretinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [34]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: Ruxolitinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Ruxolitinib by aberration of the drug's therapeutic target

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [35]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [35]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [36]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Aldefluor activity analysis
• Mechanism Description: Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [36], [37]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835H
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Aldefluor activity analysis
• Mechanism Description: Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [37]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691L
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Deep amplicon sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: In this study, we report the clinical activity of sequential therapy with sorafenib and sunitinib in children with FLT3-ITD-positive AML and the emergence of polyclonal secondary FLT3 TkD mutations during TkI therapy as identified by deep amplicon sequencing.

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [37]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y
• Resistant Drug: Sunitinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Deep amplicon sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: In this study, we report the clinical activity of sequential therapy with sorafenib and sunitinib in children with FLT3-ITD-positive AML and the emergence of polyclonal secondary FLT3 TkD mutations during TkI therapy as identified by deep amplicon sequencing.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [35]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691
• Resistant Drug: Sunitinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [35]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835
• Resistant Drug: Sunitinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Tagraxofusp

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Diphthamide biosynthesis 1 (DPH1) [38]

• Resistant Disease: Blastic plasmacytoid dendritic cell neoplasm [ICD-11: 2A60.5]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Tagraxofusp
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vivo Model: NSG mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Loss of DPH1 is sufficient to confer relative tagraxofusp resistance in AML cells. CpGs further upstream, between -300 and -80 bases from the transcription start site (TSS), showed no significant change in methylation, suggesting that increased DPH1-promoter methylation associated with tagraxofusp resistance may confer a specific advantage. Given this finding, we hypothesized that azacitidine, a DNA methyltransferase inhibitor or DNA hypomethylating agent (HMA) might reverse resistance-associated DPH1 hypermethylation and restore DPH1 expression.

Tazemetostat

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [39]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Complex-indel; p.T678_R679delinsKK (c.2032_2037delinsAAGAAG)
• Resistant Drug: Tazemetostat
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: RN2c cells; Blood; Mus musculus (Mouse); N.A.
• In Vitro Model: RN2 cells; Blood; Mus musculus (Mouse); N.A.
• In Vitro Model: Plat-E cells; Fetal kidney; Homo sapiens (Human); CVCL_B488
• Experiment for Molecule Alteration: RT-PCR

Thioguanine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [13], [27]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R238W (c.c712t)
• Resistant Drug: Thioguanine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [13], [27]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.S445F (c.c1334t)
• Resistant Drug: Thioguanine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).

Tretinoin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ZBTB16-RARA fusion protein (ZBTB16-RARA) [40]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Structural mutation; Structural variation
• Resistant Drug: Tretinoin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/PI3 signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: STAT signaling pathway; Activation; hsa04630
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: However, rarer variant translocations such as t(11;17)(q23;q21); ZBTB16-RARA or t(17;17)(q21;q21); STAT5B-RARA may result in resistance to ATRA.

Key Molecule: STAT5B-RARA fusion protein (STAT5B-RARA) [40]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Structural mutation; Structural variation
• Resistant Drug: Tretinoin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/PI3 signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: STAT signaling pathway; Activation; hsa04630
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: However, rarer variant translocations such as t(11;17)(q23;q21); ZBTB16-RARA or t(17;17)(q21;q21); STAT5B-RARA may result in resistance to ATRA.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: t(17;17)(q21;q21) (Unclear) [40]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Structural mutation; Structural variation
• Resistant Drug: Tretinoin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/PI3 signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: STAT signaling pathway; Activation; hsa04630
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: However, rarer variant translocations such as t(11;17)(q23;q21); ZBTB16-RARA or t(17;17)(q21;q21); STAT5B-RARA may result in resistance to ATRA.

Key Molecule: t(11;17)(q23;q21) (Unclear) [40]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Structural mutation; Structural variation
• Resistant Drug: Tretinoin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/PI3 signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: STAT signaling pathway; Activation; hsa04630
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: However, rarer variant translocations such as t(11;17)(q23;q21); ZBTB16-RARA or t(17;17)(q21;q21); STAT5B-RARA may result in resistance to ATRA.

Clinical Trial Drug(s) 10 drug(s) in total

Crenolanib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [22]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Sensitive Drug: Crenolanib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [41]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835H (c.2503G>C)
• Sensitive Drug: Crenolanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony assays; Plasma inhibitory assay

Enasidenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R140G (c.418C>G)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R140W (c.418C>T)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R140L (c.419G>T)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R172G (c.514A>G)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R172W (c.514A>T)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R172M (c.515G>T)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R172S (c.516G>C)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vivo Model: Acute myeloid leukemia xenograft mouse model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [42]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vivo Model: Acute myeloid leukemia xenograft mouse model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Quizartinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [43], [44]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691L
• Resistant Drug: Quizartinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Subsequent bidirectional sequencing assay
• Experiment for Drug Resistance: Vi-cell XR automated cell viability analysis
• Mechanism Description: Overall, these data support a primarily structural mechanism for AC220 resistance mediated by mutations at F691, D835 and Y842, although further studies are necessary for definitive confirmation. We speculate that the ability to retain inhibitory activity against activation loop substitutions at D835 and Y842 will require a type I FLT3 kinase inhibitor capable of effectively binding to the active, DFG-in conformation of the kinase.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [43]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835V
• Resistant Drug: Quizartinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Subsequent bidirectional sequencing assay
• Experiment for Drug Resistance: Vi-cell XR automated cell viability analysis
• Mechanism Description: Overall, these data support a primarily structural mechanism for AC220 resistance mediated by mutations at F691, D835 and Y842, although further studies are necessary for definitive confirmation. We speculate that the ability to retain inhibitory activity against activation loop substitutions at D835 and Y842 will require a type I FLT3 kinase inhibitor capable of effectively binding to the active, DFG-in conformation of the kinase.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [43]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835F
• Resistant Drug: Quizartinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Subsequent bidirectional sequencing assay
• Experiment for Drug Resistance: Vi-cell XR automated cell viability analysis
• Mechanism Description: Overall, these data support a primarily structural mechanism for AC220 resistance mediated by mutations at F691, D835 and Y842, although further studies are necessary for definitive confirmation. We speculate that the ability to retain inhibitory activity against activation loop substitutions at D835 and Y842 will require a type I FLT3 kinase inhibitor capable of effectively binding to the active, DFG-in conformation of the kinase.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [43], [45]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y
• Resistant Drug: Quizartinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Subsequent bidirectional sequencing assay
• Experiment for Drug Resistance: Vi-cell XR automated cell viability analysis
• Mechanism Description: Overall, these data support a primarily structural mechanism for AC220 resistance mediated by mutations at F691, D835 and Y842, although further studies are necessary for definitive confirmation. We speculate that the ability to retain inhibitory activity against activation loop substitutions at D835 and Y842 will require a type I FLT3 kinase inhibitor capable of effectively binding to the active, DFG-in conformation of the kinase.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [35]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691
• Resistant Drug: Quizartinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [35]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835
• Resistant Drug: Quizartinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Mutation; p.Y842C
• Resistant Drug: Quizartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with Y842C mutation was 106, the quizartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y
• Resistant Drug: Quizartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835Y mutation was 183, the quizartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835V
• Resistant Drug: Quizartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835V mutation was 563, the quizartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835I
• Resistant Drug: Quizartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835I mutation was 718, the quizartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835F
• Resistant Drug: Quizartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835F mutation was 1474, the quizartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Frameshift mutation; p.D835Del
• Resistant Drug: Quizartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835Del mutation was 320, the quizartinib IC50 value of cells without mutation was 1.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Mutation; p.F691L
• Resistant Drug: Quizartinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691L
• Resistant Drug: Quizartinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691L
• Resistant Drug: Quizartinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

Selumetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [46]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: IF-deletion; p.Q569_G613 (c.1705_1837)
• Resistant Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; .
• Experiment for Molecule Alteration: Gentra puregene assay
• Experiment for Drug Resistance: p-ERK1/2 and p-mTOR analysis

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [46]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Synonymous; p.L862L (c.2586G>C)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; .
• Experiment for Molecule Alteration: Gentra puregene assay
• Experiment for Drug Resistance: p-ERK1/2 and p-mTOR analysis

TRAIL

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27a [47]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: TRAIL
• 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: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• In Vitro Model: HL-60/ADR cells; Blood; Homo sapiens (Human); CVCL_0304
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-424 and miR-27a increase TRAIL sensitivity of acute myeloid leukemia by targeting PLAG1.

Key Molecule: hsa-mir-424 [47]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: TRAIL
• 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: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• In Vitro Model: HL-60/ADR cells; Blood; Homo sapiens (Human); CVCL_0304
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-424 and miR-27a increase TRAIL sensitivity of acute myeloid leukemia by targeting PLAG1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger protein PLAG1 (PLAG1) [47]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: TRAIL
• 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: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• In Vitro Model: HL-60/ADR cells; Blood; Homo sapiens (Human); CVCL_0304
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-424 and miR-27a increase TRAIL sensitivity of acute myeloid leukemia by targeting PLAG1.

APR-246

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [48]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.V173M (c.517G>A)
• Sensitive Drug: APR-246
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; .
• Experiment for Molecule Alteration: TP53 gene mutation status analysis
• Experiment for Drug Resistance: Pharmacokinetic Analysis
• Mechanism Description: The missense mutation p.V173M (c.517G>A) in gene TP53 cause the sensitivity of APR-246 by unusual activation of pro-survival pathway

E6201

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [49]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Sensitive Drug: E6201
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: NOG mouse; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; FACS assay
• Mechanism Description: E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [49]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835G (c.2504A>G)
• Sensitive Drug: E6201
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: NOG mouse; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; FACS assay
• Mechanism Description: E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.

NS-018

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [50]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.A572V (c.1715C>T)
• Resistant Drug: NS-018
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Sf9 cells; Ovary; Homo sapiens (Human); CVCL_0549
• Experiment for Molecule Alteration: Colony formation assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.A572V (c.1715C>T) in gene JAK3 cause the resistance of NS-018 by aberration of the drug's therapeutic target

BAY1436032

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [51]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132S (c.394C>A)
• Sensitive Drug: BAY1436032
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [51]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132G (c.394C>G)
• Sensitive Drug: BAY1436032
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [51]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Sensitive Drug: BAY1436032
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [51]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: BAY1436032
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [51]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132L (c.395G>T)
• Sensitive Drug: BAY1436032
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Trichostatin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [52]

• Resistant Disease: Adult acute myeloid leukemia [ICD-11: 2A60.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Key Molecule: hsa-miR-199a-5p [52]

• Resistant Disease: Adult acute myeloid leukemia [ICD-11: 2A60.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Key Molecule: hsa-mir-30d [52]

• Resistant Disease: Adult acute myeloid leukemia [ICD-11: 2A60.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Endoplasmic reticulum chaperone BiP (HSPA5) [52]

• Resistant Disease: Adult acute myeloid leukemia [ICD-11: 2A60.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Discontinued Drug(s) 2 drug(s) in total

SU5614

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [53]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: IF-deletion; p.Q569_G613 (c.1705_1837)
• Resistant Drug: SU5614
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The if-deletion p.Q569_G613 (c.1705_1837) in gene FLT3 cause the resistance of SU5614 by unusual activation of pro-survival pathway.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [54]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Resistant Drug: SU5614
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.D835Y (c.2503G>T) in gene FLT3 cause the resistance of SU5614 by unusual activation of pro-survival pathway

Tandutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [55]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835V (c.2504A>T)
• Resistant Drug: Tandutinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Celltiter96AQueousOne solution proliferation assay
• Mechanism Description: The missense mutation p.D835V (c.2504A>T) in gene FLT3 cause the resistance of Tandutinib by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [56]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Duplication; p.R595_L601 (c.1783_1803)
• Sensitive Drug: Tandutinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vitro Model: RS4 cells; Bone marrow; Homo sapiens (Human); CVCL_0093
• In Vitro Model: AML193 cells; Peripheral blood; Homo sapiens (Human); CVCL_1071
• In Vivo Model: Athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The duplication p.R595_L601 (c.1783_1803) in gene FLT3 cause the sensitivity of Tandutinib by aberration of the drug's therapeutic target.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [56]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: IF-insertion; p.E598_Y599insGLVQVTGSSDNEYFYVDFREYE (c.1794_1795insGGTCTTGTACAAGTAACAGGTAGCAGCGACAACGAGTATTTTTATGTAGACTTTAGGGAGTATGAG)
• Sensitive Drug: Tandutinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vitro Model: RS4 cells; Bone marrow; Homo sapiens (Human); CVCL_0093
• In Vitro Model: AML193 cells; Peripheral blood; Homo sapiens (Human); CVCL_1071
• In Vivo Model: Athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The if-insertion p.E598_Y599insGLVQVTGSSDNEYFYVDFREYE (c.1794_1795insGGTCTTGTACAAGTAACAGGTAGCAGCGACAACGAGTATTTTTATGTAGACTTTAGGGAGTATGAG) in gene FLT3 cause the sensitivity of Tandutinib by aberration of the drug's therapeutic target.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [56]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: IF-insertion; p.Y599_D600insGLYVDFREYEY (c.1798_1799insGTCTTTATGTAGACTTTAGGGAGTATGAGTATG)
• Sensitive Drug: Tandutinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vitro Model: RS4 cells; Bone marrow; Homo sapiens (Human); CVCL_0093
• In Vitro Model: AML193 cells; Peripheral blood; Homo sapiens (Human); CVCL_1071
• In Vivo Model: Athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The if-insertion p.Y599_D600insGLYVDFREYEY (c.1798_1799insGTCTTTATGTAGACTTTAGGGAGTATGAGTATG) in gene FLT3 cause the sensitivity of Tandutinib by aberration of the drug's therapeutic target.

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

A-1155463

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [57]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: A-1155463
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SCLC cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: NHL cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: SCID and SCID-bg mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony formation assay

AGI-6780

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [58]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Sensitive Drug: AGI-6780
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Blood; .
• Mechanism Description: The missense mutation p.R140Q (c.419G>A) in gene IDH2 cause the sensitivity of AGI-6780 by aberration of the drug's therapeutic target

Alpelisib/Binimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [59]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.G12D (c.35G>A)
• Sensitive Drug: Alpelisib/Binimetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NOMO1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• In Vitro Model: THP1 cell; Peripheral blood; Homo sapiens (Human); CVCL_0006
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

ALRN-6924

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [60]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R248Q (c.743G>A)
• Resistant Drug: ALRN-6924
• Experimental Note: Identified from the Human Clinical Data

BPR1J373

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [61]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• Sensitive Drug: BPR1J373
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST1 assay; BD FACSCalibur assay; FACS assay
• Mechanism Description: BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest.

BPTES

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [62]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Sensitive Drug: BPTES
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: AML cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Manually cell counting assay

GSK321

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [63]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Sensitive Drug: GSK321
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT-1080 cells; Acetabulum; Homo sapiens (Human); CVCL_0317
• In Vivo Model: Male CD-1 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Diaphorase/resazurin coupled assay; Colony formation assay

NSC348884

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Nucleophosmin (NPM1) [64]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: FS-deletion; p.W288fs (c.863_864)
• Sensitive Drug: NSC348884
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OCI-AML3 cells; Blood; Homo sapiens (Human); CVCL_1844
• In Vitro Model: HL-60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Colony-forming assay
• Mechanism Description: The fs-deletion p.W288fs (c.863_864) in gene NPM1 cause the sensitivity of NSC348884 by aberration of the drug's therapeutic target.

SHP099

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [65]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Resistant Drug: SHP099
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559

Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [65]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D61Y (c.181G>T)
• Resistant Drug: SHP099
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559

Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [65]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.A72V (c.215C>T)
• Resistant Drug: SHP099
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [65]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.E69K (c.205G>A)
• Sensitive Drug: SHP099
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559

Investigative Drug(s) 8 drug(s) in total

AG1296

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [66]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: IF-deletion; p.Q569_G613 (c.1705_1837)
• Sensitive Drug: AG1296
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Immunoprecipitation and immunoblot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The if-deletion p.Q569_G613 (c.1705_1837) in gene FLT3 cause the sensitivity of AG1296 by unusual activation of pro-survival pathway.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [67]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835V (c.2504A>T)
• Sensitive Drug: AG1296
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell proliferation Kit II XTT assay
• Mechanism Description: The missense mutation p.D835V (c.2504A>T) in gene FLT3 cause the sensitivity of AG1296 by unusual activation of pro-survival pathway

Azacitidine/Sorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [68]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: IF-insertion; p.Y599_D600insSTDNEYFYVDFREYEY (c.1797_1798insAGCACAGACAACGAGTATTTTTATGTAGACTTTAGGGAGTATGAGTAT)
• Sensitive Drug: Azacitidine/Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Mechanism Description: The if-insertion p.Y599_D600insSTDNEYFYVDFREYEY (c.1797_1798insAGCACAGACAACGAGTATTTTTATGTAGACTTTAGGGAGTATGAGTAT) in gene FLT3 cause the sensitivity of Azacitidine + Sorafenib by unusual activation of pro-survival pathway.

Cytarabine/Daunorubicin/Midostaurin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [69]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.I836 (c.2506_2508)
• Sensitive Drug: Cytarabine/Daunorubicin/Midostaurin
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [69]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835 (c.2503_2505)
• Sensitive Drug: Cytarabine/Daunorubicin/Midostaurin
• Experimental Note: Identified from the Human Clinical Data

GO6976

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [70]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: GO6976
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: Mo7E cells; Peripheral blood; Homo sapiens (Human); CVCL_2106
• In Vitro Model: FDCP1 cells; Bone marrow; Mus musculus (Mouse); CVCL_2039
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Go6976 by unusual activation of pro-survival pathway

IDH2 inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [71]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Sensitive Drug: IDH2 inhibitors
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [71]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Sensitive Drug: IDH2 inhibitors
• Experimental Note: Identified from the Human Clinical Data

Induction therapy

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Nucleophosmin (NPM1) [72]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: FS-deletion; p.W288fs (c.863_864)
• Sensitive Drug: Induction therapy
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Immunostaining assay
• Mechanism Description: The fs-deletion p.W288fs (c.863_864) in gene NPM1 cause the sensitivity of Induction Therapy by unusual activation of pro-survival pathway.

Pyridone 6

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [73]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.Q501H (c.1503G>T)
• Sensitive Drug: Pyridone 6
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.Q501H (c.1503G>T) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [73]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R657Q (c.1970G>A)
• Sensitive Drug: Pyridone 6
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.R657Q (c.1970G>A) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [73]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.I87T (c.260T>C)
• Sensitive Drug: Pyridone 6
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.I87T (c.260T>C) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Tyrosine kinase inhibitor

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [74]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Tyrosine kinase inhibitor
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole exome capture sequencing assay
• Experiment for Drug Resistance: karyotyping assay
• Mechanism Description: Treatment with TkIs selectively leads to secondary mutations in the activation loop domain of the gene, where those who relapse after exposure to TkI show evolution of secondary FLT3 mutations that are associated with TkI resistance.

References

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