Drug Information

Drug (ID: DG00174) and It's Reported Resistant Information

• Name: Dasatinib
• Synonyms: Sprycel (TN); BMS 354825; BMS-354825; BMS-354825, Sprycel, BMS354825, Dasatinib; BMS354825; Dasatinib (USAN); Dasatinib [USAN]; Dasatinib anhydrous; Dasatinib, BMS 354825; Dasatinibum; Sprycel; Spyrcel
• Indication:
  In total 2 Indication(s)
  Myeloproliferative neoplasm [ICD-11: 2A22]; Approved; [1]
  Multiple myeloma [ICD-11: 2A83]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  Breast cancer [ICD-11: 2C60]; [3]
  Chronic myeloid leukemia [ICD-11: 2A20]; [4], [5], [6]
  Mature T-cell lymphoma [ICD-11: 2A90]; [7]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Chronic myeloid leukemia [ICD-11: 2A20]; [1]
  Lung cancer [ICD-11: 2C25]; [8]
• Target: Fusion protein Bcr-Abl (Bcr-Abl); BCR_HUMAN-ABL1_HUMAN; [1]
• Target: Fyn tyrosine protein kinase (FYN); FYN_HUMAN; [1]
• Target: LCK tyrosine protein kinase (LCK); LCK_HUMAN; [1]
• Target: Proto-oncogene c-Src (SRC); SRC_HUMAN; [1]
• Formula: C22H26ClN7O2S
• IsoSMILES: CC1=C(C(=CC=C1)Cl)NC(=O)C2=CN=C(S2)NC3=CC(=NC(=N3)C)N4CCN(CC4)CCO
• InChI: 1S/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27)
• InChIKey: ZBNZXTGUTAYRHI-UHFFFAOYSA-N
• PubChem CID: 3062316
• ChEBI ID: CHEBI:49375
• TTD Drug ID: D0E6XR
• VARIDT ID: DR00182
• INTEDE ID: DR0423
• DrugBank ID: DB01254

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [8]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.17E-11; Fold-change: -1.61E-01; Z-score: -7.19E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Abl/RAS/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Reduced miR-3127-5p expression promotes NSCLC proliferation/invasion and contributes to dasatinib sensitivity via the c-Abl/Ras/ERk pathway.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-3127-5p [8]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Abl/RAS/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Reduced miR-3127-5p expression promotes NSCLC proliferation/invasion and contributes to dasatinib sensitivity via the c-Abl/Ras/ERk pathway.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase ULK1 (ULK1) [9]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.52E-01; Fold-change: -2.18E-02; Z-score: -4.52E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR106a/ULk1 signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Resazurin conversion assay
• Mechanism Description: Src inhibition results in autophagy activation in NSCLC cell lines. Combining Src with autophagy inhibition results in significant cell death. Induction of ULk1 upon Scr inhibition allows for autophagy activation. Src inhibition causes induction of the ULk1 targeting microRNA-106a. Expression of the "oncogenic" miR-106a sensitizes NSCLC cells to Src inhibition.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-106a [9]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR106a/ULk1 signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Resazurin conversion assay
• Mechanism Description: Src inhibition results in autophagy activation in NSCLC cell lines. Combining Src with autophagy inhibition results in significant cell death. Induction of ULk1 upon Scr inhibition allows for autophagy activation. Src inhibition causes induction of the ULk1 targeting microRNA-106a. Expression of the "oncogenic" miR-106a sensitizes NSCLC cells to Src inhibition.

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [10], [11]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.T315I
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.89 Å; PDB: 4XEY
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.17 Å; PDB: 5MO4

RMSD: 1.69; TM score: 0.88225; Amino acid change: T315I

• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [5], [6], [10]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.G250E
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.17 Å; PDB: 5MO4
• Mutant Type Structure: Method: Solution NMR; Resolution: N.A.; PDB: 6XRG

RMSD: 2.4; TM score: 0.79586; Amino acid change: G250E

• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [4], [5], [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.F317L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: After 13 months of therapy a progression of disease to accelerated phase was detected and a second mutational screening analysis performed at that time revealed the absence of M244 V and the appearance of M351T mutation. After 14 months of therapy, a third mutational analysis was performed which revealed the disappearance of M351T mutation and the acquisition of a new F317L mutation.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [10], [11]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.Y253H
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.V338F
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [5], [6], [13]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.V299L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.V268A
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7], [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.T315A
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.Q252H
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.M351T
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [14], [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.M244V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [14], [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.L387M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.L384M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.L298V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.L248V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.H396R
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [14], [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.F359V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.F359C
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.F317V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.F317I
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.F317C
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.F311L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.E459K
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.E355G
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence 23223358. We confirmed the high frequency of SFks involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFks deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFks kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.E255V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.E255K
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.D325G
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Sanger sequencing assay
• Mechanism Description: For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [5]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.T495R
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Mechanism Description: The most common mechanism of acquired resistance in CML in imatinib era is the acquisition of BCR-ABL kinase domain mutations with decreased sensitivity to the drug. Our findings demonstrate the potential hazards of sequential kinase inhibitor therapy and suggest a role for a combination of ABL kinase inhibitors, perhaps including drugs with different mechanisms of action, to prevent the outgrowth of cells harboring drug-resistant BCR-ABL mutations.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [14]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.M388L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: RNA sequencing assay
• Mechanism Description: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor (TkI) treatment. In addition to 9 point mutations (G250E / F317L, F359V, L387M, Y253H, M388L, M244V, T315I, D276G), 35 bp insertion between exons 8 and 9 and deletion exon 7 were detected. Our results demonstrate that direct sequencing is suitable for routine clinical monitoring patients with CML and may be useful for optimizing therapy.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [14]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.D276G
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: RNA sequencing assay
• Mechanism Description: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor (TkI) treatment. In addition to 9 point mutations (G250E / F317L, F359V, L387M, Y253H, M388L, M244V, T315I, D276G), 35 bp insertion between exons 8 and 9 and deletion exon 7 were detected. Our results demonstrate that direct sequencing is suitable for routine clinical monitoring patients with CML and may be useful for optimizing therapy.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.Y353H
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: We confirmed the high frequency of SFks involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFks deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFks kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.Y253F
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: We confirmed the high frequency of SFks involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFks deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFks kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.V379I
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: We confirmed the high frequency of SFks involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFks deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFks kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.L273M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: We confirmed the high frequency of SFks involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFks deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFks kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.V299L
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.F317L
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [12]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.E255K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa_circ_BA9.3 [1]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCk reagent assay; Flow cytometry assay
• Mechanism Description: CircBA9.3 promoted cell proliferation and reduced the sensitivity of leukaemic cells to TkIs through up-regulation of the ABL1 and BCR-ABL1 protein expression levels.

Key Molecule: hsa-miR-29a-3p [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR29a-3p observed in CML LSCs led to the down-regulation of its target TET2 and conferred TkI-resistance to CML LSCs in vitro.

Key Molecule: hsa-miR-494-3p [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: miR494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TkI-induced apoptosis.

Key Molecule: hsa-miR-660-5p [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR660-5p observed in CML LSCs led to the down-regulation of its target EPAS1 and conferred TkI-resistance to CML LSCs in vitro.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.D444Y
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: We confirmed the high frequency of SFks involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFks deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFks kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [16]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562-ABCG2 cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of ABCG2 on the membrane surface of CML cells contributes to decreased TKI efficacy. This study demonstrates for the first time that the concomitant use of febuxostat enhances the efficacy of dasatinib in patients with CML. This is at least, in part, by the inhibition of ABCG2-mediated dasatinib excretion from CML cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [17], [18]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.G12V
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.98 Å; PDB: 7SCW
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.96 Å; PDB: 7SCX

RMSD: 0.47; TM score: 0.99104; Amino acid change: G12V

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT signaling pathway; Activation; hsa04030
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• 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: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [1]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: CCk reagent assay; Flow cytometry assay
• Mechanism Description: CircBA9.3 promoted cell proliferation and reduced the sensitivity of leukaemic cells to TkIs through up-regulation of the ABL1 and BCR-ABL1 protein expression levels.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [1]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: CCk reagent assay; Flow cytometry assay
• Mechanism Description: CircBA9.3 promoted cell proliferation and reduced the sensitivity of leukaemic cells to TkIs through up-regulation of the ABL1 and BCR-ABL1 protein expression levels.

Key Molecule: Myc proto-oncogene protein (MYC) [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: miR494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TkI-induced apoptosis.

Key Molecule: Hypoxia-inducible factor 2-alpha (EPAS1) [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR660-5p observed in CML LSCs led to the down-regulation of its target EPAS1 and conferred TkI-resistance to CML LSCs in vitro.

Key Molecule: Methylcytosine dioxygenase TET2 (TET2) [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR29a-3p observed in CML LSCs led to the down-regulation of its target TET2 and conferred TkI-resistance to CML LSCs in vitro.

Key Molecule: Extracellular signal-regulated kinases 1/2 (ERK1/2) [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/DR cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye staining assay
• Mechanism Description: We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML.

Key Molecule: Extracellular signal-regulated kinases 1/2 (ERK1/2) [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/DR cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye staining assay
• Mechanism Description: We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML.

Key Molecule: MAP kinase kinase kinase 8 (TPL2/COT) [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/DR cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye staining assay
• Mechanism Description: We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML.

Key Molecule: MAP kinase kinase kinase 8 (TPL2/COT) [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/DR cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye staining assay
• Mechanism Description: We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML.

Key Molecule: Proto-oncogene serine/threonine-protein kinase mos (MOS) [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/DR cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye staining assay
• Mechanism Description: We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-217 [20]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR217/AGR2 signaling pathway; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• In Vitro Model: kCL22 cells; Pleural effusion; Homo sapiens (Human); CVCL_2091
• In Vivo Model: NRG mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by downregulating pro-oncogenic anterior gradient 2.

Key Molecule: hsa-mir-217 [21]

• Sensitive Disease: Chronic myelogenous Ph(+) leukemia [ICD-11: 2A20.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bcr/Abl-expressing k562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562DR cells; Blood; Homo sapiens (Human); CVCL_4V59
• In Vitro Model: K562NR cells; Blood; Homo sapiens (Human); CVCL_4V63
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Forced expression of miR-217 inhibited expression of DNMT3A through a miR-217-binding site within the 3'-untranslated region of DNMT3A and sensitized these cells to growth inhibition mediated by the TkI. long-term exposure of CML k562 cells to ABL TkI such as dasatinib and nilotinib decreased the levels of miR-217 and increased the levels of DNMT1 and DNMT3A, as well as resulting in acquisition of TkI resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Anterior gradient protein 2 homolog (AGR2) [20]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR217/AGR2 signaling pathway; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• In Vitro Model: kCL22 cells; Pleural effusion; Homo sapiens (Human); CVCL_2091
• In Vivo Model: NRG mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by downregulating pro-oncogenic anterior gradient 2.

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [21]

• Sensitive Disease: Chronic myelogenous Ph(+) leukemia [ICD-11: 2A20.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bcr/Abl-expressing k562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562DR cells; Blood; Homo sapiens (Human); CVCL_4V59
• In Vitro Model: K562NR cells; Blood; Homo sapiens (Human); CVCL_4V63
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Forced expression of miR-217 inhibited expression of DNMT3A through a miR-217-binding site within the 3'-untranslated region of DNMT3A and sensitized these cells to growth inhibition mediated by the TkI. long-term exposure of CML k562 cells to ABL TkI such as dasatinib and nilotinib decreased the levels of miR-217 and increased the levels of DNMT1 and DNMT3A, as well as resulting in acquisition of TkI resistance.

Mature T-cell lymphoma [ICD-11: 2A90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7]

• Resistant Disease: Acute T-cell lymphocytic leukemia [ICD-11: 2A90.5]
• Molecule Alteration: Missense mutation; p.F317R
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Tritiated thymidine incorporation assay
• Mechanism Description: Mutations may impair TkI activity by directly or indirectly impairing the drug binding to the protein. We report the discovery of three new BCR/ABL mutations, L248R, T315V, and F317R identified in two patients with CML (L248R and T315V) and in one patient with Ph+ acute lymphoblastic leukemia (ALL) (F317R).

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [2], [22]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.T315I
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.89 Å; PDB: 4XEY
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.17 Å; PDB: 5MO4

RMSD: 1.69; TM score: 0.88225; Amino acid change: T315I

• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Flow cytometry assay; Analysis of disease free and overall survival assay
• Mechanism Description: Mutations were frequently detected at relapse. Among 17 patients analyzed, a T315I mutation was detected in 12, E255k in 1, and no BCR-ABL mutations in 4 (25886620). Thirteen relapsed patients had mutational analysis and 7 had ABL mutations (4 T315I, 1 F359V, and 2 V299L).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [2]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.E255K
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Mutations were frequently detected at relapse. Among 17 patients analyzed, a T315I mutation was detected in 12, E255k in 1, and no BCR-ABL mutations in 4.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [22]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.V299L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Analysis of disease free and overall survival assay
• Mechanism Description: Thirteen relapsed patients had mutational analysis and 7 had ABL mutations (4 T315I, 1 F359V, and 2 V299L).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [22]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.F359V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Analysis of disease free and overall survival assay
• Mechanism Description: Thirteen relapsed patients had mutational analysis and 7 had ABL mutations (4 T315I, 1 F359V, and 2 V299L).

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Molecule Alteration: Missense mutation; p.E711K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

References

• Ref 1: CircBA9.3 supports the survival of leukaemic cells by up-regulating c-ABL1 or BCR-ABL1 protein levels. Blood Cells Mol Dis. 2018 Nov;73:38-44. doi: 10.1016/j.bcmd.2018.09.002. Epub 2018 Sep 14.
• Ref 2: Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15;118(25):6521-8. doi: 10.1182/blood-2011-05-351403. Epub 2011 Sep 19.
• Ref 3: Circulating-free DNA Mutation Associated with Response of Targeted Therapy in Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer. Chin Med J (Engl). 2017 Mar 5;130(5):522-529. doi: 10.4103/0366-6999.200542.
• Ref 4: Sequential development of mutant clones in an imatinib resistant chronic myeloid leukaemia patient following sequential treatment with multiple tyrosine kinase inhibitors: an emerging problem . Cancer Chemother Pharmacol. 2009 Jun;64(1):195-7. doi: 10.1007/s00280-008-0905-5. Epub 2009 Jan 21.
• Ref 5: Complexity of BCR-ABL kinase domain mutations during the course of therapy with tyrosine kinase inhibitors in chronic myeloid leukemia. Am J Hematol. 2009 Apr;84(4):256-7. doi: 10.1002/ajh.21366.
• Ref 6: Longitudinal studies of SRC family kinases in imatinib- and dasatinib-resistant chronic myelogenous leukemia patients. Leuk Res. 2011 Jan;35(1):38-43. doi: 10.1016/j.leukres.2010.06.030. Epub 2010 Jul 29.
• Ref 7: Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors. Am J Hematol. 2012 Nov;87(11):E125-8. doi: 10.1002/ajh.23338. Epub 2012 Oct 9.
• Ref 8: Reduced miR-3127-5p expression promotes NSCLC proliferation/invasion and contributes to dasatinib sensitivity via the c-Abl/Ras/ERK pathway. Sci Rep. 2014 Oct 6;4:6527. doi: 10.1038/srep06527.
• Ref 9: MicroRNA-106a targets autophagy and enhances sensitivity of lung cancer cells to Src inhibitors. Lung Cancer. 2017 May;107:73-83. doi: 10.1016/j.lungcan.2016.06.004. Epub 2016 Jun 14.
• Ref 10: A novel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib resistance: sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis. Int J Hematol. 2011 Feb;93(2):237-242. doi: 10.1007/s12185-011-0766-2. Epub 2011 Jan 25.
• Ref 11: Outcome of patients with chronic myeloid leukemia with multiple ABL1 kinase domain mutations receiving tyrosine kinase inhibitor therapy. Haematologica. 2011 Jun;96(6):918-21. doi: 10.3324/haematol.2010.039321. Epub 2011 Feb 28.
• Ref 12: BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood. 2013 Jan 17;121(3):489-98. doi: 10.1182/blood-2012-05-431379. Epub 2012 Dec 5.
• Ref 13: Early detection and quantification of mutations in the tyrosine kinase domain of chimerical BCR-ABL1 gene combining high-resolution melting analysis and mutant-allele specific quantitative polymerase chain reaction. Leuk Lymphoma. 2013 Mar;54(3):598-606. doi: 10.3109/10428194.2012.718767. Epub 2012 Aug 31.
• Ref 14: Use of direct sequencing for detection of mutations in the BCR-ABL kinase domain in Slovak patients with chronic myeloid leukemia. Neoplasma. 2011;58(6):548-53. doi: 10.4149/neo_2011_06_548.
• Ref 15: Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells. Oncotarget. 2017 Jul 25;8(30):49451-49469. doi: 10.18632/oncotarget.17706.
• Ref 16: Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells. Biomed Pharmacother. 2024 Dec;181:117709.
• Ref 17: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013 Aug 8;122(6):872-84. doi: 10.1182/blood-2013-05-501569. Epub 2013 Jun 26.
• Ref 18: Dissecting Genomic Aberrations in Myeloproliferative Neoplasms by Multiplex-PCR and Next Generation Sequencing. PLoS One. 2015 Apr 20;10(4):e0123476. doi: 10.1371/journal.pone.0123476. eCollection 2015.
• Ref 19: Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells. Cell Prolif. 2023 Jun;56(6):e13420.
• Ref 20: miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2. Exp Hematol. 2018 Dec;68:80-88.e2. doi: 10.1016/j.exphem.2018.09.001. Epub 2018 Sep 5.
• Ref 21: Downregulation of miR-217 correlates with resistance of Ph(+) leukemia cells to ABL tyrosine kinase inhibitors. Cancer Sci. 2014 Mar;105(3):297-307. doi: 10.1111/cas.12339. Epub 2014 Jan 30.
• Ref 22: Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. doi: 10.1002/cncr.29646. Epub 2015 Aug 26.