Drug Information
Drug (ID: DG00174) and It's Reported Resistant Information
Name |
Dasatinib
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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
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Indication |
In total 2 Indication(s)
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Structure | |||||
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]
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]
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Target | Fusion protein Bcr-Abl (Bcr-Abl) | BCR_HUMAN-ABL1_HUMAN | [1] | ||
Fyn tyrosine protein kinase (FYN) | FYN_HUMAN | [1] | |||
LCK tyrosine protein kinase (LCK) | LCK_HUMAN | [1] | |||
Proto-oncogene c-Src (SRC) | SRC_HUMAN | [1] | |||
Click to Show/Hide the Molecular Information and External Link(s) of This Drug | |||||
Formula |
C22H26ClN7O2S
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IsoSMILES |
CC1=C(C(=CC=C1)Cl)NC(=O)C2=CN=C(S2)NC3=CC(=NC(=N3)C)N4CCN(CC4)CCO
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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)
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InChIKey |
ZBNZXTGUTAYRHI-UHFFFAOYSA-N
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PubChem CID | |||||
ChEBI ID | |||||
TTD Drug ID | |||||
VARIDT ID | |||||
INTEDE ID | |||||
DrugBank ID |
Type(s) of Resistant Mechanism of This Drug
ADTT: Aberration of the Drug's Therapeutic Target
EADR: Epigenetic Alteration of DNA, RNA or Protein
UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Chronic myeloid leukemia [ICD-11: 2A20]
Drug Resistance Data Categorized by Their Corresponding Mechanisms | ||||
Aberration of the Drug's Therapeutic Target (ADTT) | ||||
Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) | [4], [5], [6] | |||
Molecule Alteration | Missense mutation | p.F317L |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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], [9], [10] | |||
Molecule Alteration | Missense mutation | p.Y253H |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.V338F |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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], [12] | |||
Molecule Alteration | Missense mutation | p.V299L |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.V268A |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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], [9], [10] | |||
Molecule Alteration | Missense mutation | p.T315I |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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], [11] | |||
Molecule Alteration | Missense mutation | p.T315A |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.Q252H |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.M351T |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [13], [11] | |||
Molecule Alteration | Missense mutation | p.M244V |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [13], [11] | |||
Molecule Alteration | Missense mutation | p.L387M |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.L384M |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.L298V |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.L248V |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.H396R |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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], [9] | |||
Molecule Alteration | Missense mutation | p.G250E |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [13], [11] | |||
Molecule Alteration | Missense mutation | p.F359V |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.F359C |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.F317V |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.F317I |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.F317C |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.F311L |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.E459K |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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], [11] | |||
Molecule Alteration | Missense mutation | p.E355G |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.E255V |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.E255K |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.D325G |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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] | |||
Molecule Alteration | Missense mutation | p.T495R |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [13] | |||
Molecule Alteration | Missense mutation | p.M388L |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [13] | |||
Molecule Alteration | Missense mutation | p.D276G |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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] | |||
Molecule Alteration | Missense mutation | p.Y353H |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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] | |||
Molecule Alteration | Missense mutation | p.Y253F |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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] | |||
Molecule Alteration | Missense mutation | p.V379I |
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Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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] | |||
Molecule Alteration | Missense mutation | p.L273M |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.V299L |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.F317L |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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) | [11] | |||
Molecule Alteration | Missense mutation | p.E255K |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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] | |||
Molecule Alteration | Expression | Up-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Inhibition | hsa04210 | |
Cell proliferation | Activation | hsa05200 | ||
In Vitro Model | K562 cells | Blood | Homo sapiens (Human) | CVCL_0004 |
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 | [14] | |||
Molecule Alteration | Expression | Up-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | Lin-CD34+CD38- cells | Bone | Homo sapiens (Human) | N.A. |
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 | [14] | |||
Molecule Alteration | Expression | Down-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | Lin-CD34+CD38- cells | Bone | Homo sapiens (Human) | N.A. |
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 | [14] | |||
Molecule Alteration | Expression | Up-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | Lin-CD34+CD38- cells | Bone | Homo sapiens (Human) | N.A. |
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] | |||
Molecule Alteration | Missense mutation | p.D444Y |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
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. | |||
Unusual Activation of Pro-survival Pathway (UAPP) | ||||
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) | [1] | |||
Molecule Alteration | Expression | Up-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Inhibition | hsa04210 | |
Cell proliferation | Activation | hsa05200 | ||
In Vitro Model | K562 cells | Blood | Homo sapiens (Human) | CVCL_0004 |
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] | |||
Molecule Alteration | Expression | Up-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Inhibition | hsa04210 | |
Cell proliferation | Activation | hsa05200 | ||
In Vitro Model | K562 cells | Blood | Homo sapiens (Human) | CVCL_0004 |
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) | [14] | |||
Molecule Alteration | Expression | Up-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | Lin-CD34+CD38- cells | Bone | Homo sapiens (Human) | N.A. |
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) | [14] | |||
Molecule Alteration | Expression | Down-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | Lin-CD34+CD38- cells | Bone | Homo sapiens (Human) | N.A. |
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) | [14] | |||
Molecule Alteration | Expression | Down-regulation |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | Lin-CD34+CD38- cells | Bone | Homo sapiens (Human) | N.A. |
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: GTPase Nras (NRAS) | [15], [16] | |||
Molecule Alteration | Missense mutation | p.G12V |
||
Resistant Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Identified from the Human Clinical Data | |||
Cell Pathway Regulation | JAKT2/STAT signaling pathway | Activation | hsa04030 | |
RAF/KRAS/MEK signaling pathway | Activation | hsa04010 | ||
In Vitro Model | HL60 cells | Peripheral blood | Homo sapiens (Human) | CVCL_0002 |
U937 cells | Blood | Homo sapiens (Human) | CVCL_0007 | |
K562 cells | Blood | Homo sapiens (Human) | CVCL_0004 | |
KCL-22 cells | Bone marrow | Homo sapiens (Human) | CVCL_2091 | |
Sup-B15 cells | Bone marrow | Homo sapiens (Human) | CVCL_0103 | |
HEL cells | Blood | Homo sapiens (Human) | CVCL_0001 | |
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. |
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms | ||||
Epigenetic Alteration of DNA, RNA or Protein (EADR) | ||||
Key Molecule: hsa-mir-217 | [17] | |||
Molecule Alteration | Expression | Up-regulation |
||
Sensitive Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Activation | hsa04210 | |
Cell viability | Inhibition | hsa05200 | ||
miR217/AGR2 signaling pathway | Regulation | hsa05206 | ||
In Vitro Model | K562 cells | Blood | Homo sapiens (Human) | CVCL_0004 |
Ku812 cells | Bone marrow | Homo sapiens (Human) | CVCL_0379 | |
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 | [18] | |||
Molecule Alteration | Expression | Up-regulation |
||
Sensitive Disease | Chronic myelogenous Ph(+) leukemia [ICD-11: 2A20.1] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | Bcr/Abl-expressing k562 cells | Blood | Homo sapiens (Human) | CVCL_0004 |
K562DR cells | Blood | Homo sapiens (Human) | CVCL_4V59 | |
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) | [17] | |||
Molecule Alteration | Expression | Down-regulation |
||
Sensitive Disease | Chronic myeloid leukemia [ICD-11: 2A20.0] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Activation | hsa04210 | |
Cell viability | Inhibition | hsa05200 | ||
miR217/AGR2 signaling pathway | Regulation | hsa05206 | ||
In Vitro Model | K562 cells | Blood | Homo sapiens (Human) | CVCL_0004 |
Ku812 cells | Bone marrow | Homo sapiens (Human) | CVCL_0379 | |
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) | [18] | |||
Molecule Alteration | Expression | Down-regulation |
||
Sensitive Disease | Chronic myelogenous Ph(+) leukemia [ICD-11: 2A20.1] | |||
Experimental Note | Identified from the Human Clinical Data | |||
In Vitro Model | Bcr/Abl-expressing k562 cells | Blood | Homo sapiens (Human) | CVCL_0004 |
K562DR cells | Blood | Homo sapiens (Human) | CVCL_4V59 | |
K562NR cells | Blood | Homo sapiens (Human) | CVCL_4V63 | |
In Vivo Model | BALB/c nude mouse xenograft model | Mus musculus | ||
Experiment for Molecule Alteration |
Western blotting analysis | |||
Experiment for Drug Resistance |
MTT assay | |||
Mechanism Description | 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] | |||
Molecule Alteration | Missense mutation | p.F317R |
||
Resistant Disease | Acute T-cell lymphocytic leukemia [ICD-11: 2A90.5] | |||
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], [19] | |||
Molecule Alteration | Missense mutation | p.T315I |
||
Resistant Disease | Acute lymphocytic leukemia [ICD-11: 2B33.0] | |||
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] | |||
Molecule Alteration | Missense mutation | p.E255K |
||
Resistant Disease | Acute lymphocytic leukemia [ICD-11: 2B33.0] | |||
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) | [19] | |||
Molecule Alteration | Missense mutation | p.V299L |
||
Resistant Disease | Acute lymphocytic leukemia [ICD-11: 2B33.0] | |||
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) | [19] | |||
Molecule Alteration | Missense mutation | p.F359V |
||
Resistant Disease | Acute lymphocytic leukemia [ICD-11: 2B33.0] | |||
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). |
Lung cancer [ICD-11: 2C25]
Drug Resistance Data Categorized by Their Corresponding Mechanisms | ||||
Epigenetic Alteration of DNA, RNA or Protein (EADR) | ||||
Key Molecule: hsa-miR-3127-5p | [8] | |||
Molecule Alteration | Expression | Up-regulation |
||
Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Abl/RAS/ERK signaling pathway | Activation | hsa04010 | |
Cell proliferation | Activation | hsa05200 | ||
In Vitro Model | H292 cells | Lung | Homo sapiens (Human) | CVCL_0455 |
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. | |||
Unusual Activation of Pro-survival Pathway (UAPP) | ||||
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) | [8] | |||
Molecule Alteration | Expression | Down-regulation |
||
Resistant Disease | Non-small cell lung cancer [ICD-11: 2C25.Y] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Abl/RAS/ERK signaling pathway | Activation | hsa04010 | |
Cell proliferation | Activation | hsa05200 | ||
In Vitro Model | H292 cells | Lung | Homo sapiens (Human) | CVCL_0455 |
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. |
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms | ||||
Epigenetic Alteration of DNA, RNA or Protein (EADR) | ||||
Key Molecule: hsa-mir-106a | [20] | |||
Molecule Alteration | Expression | Up-regulation |
||
Sensitive Disease | Lung cancer [ICD-11: 2C25.5] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Activation | hsa04210 | |
miR106a/ULk1 signaling pathway | Inhibition | hsa05206 | ||
In Vitro Model | A549 cells | Lung | Homo sapiens (Human) | CVCL_0023 |
H460 cells | Lung | Homo sapiens (Human) | CVCL_0459 | |
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. | |||
Unusual Activation of Pro-survival Pathway (UAPP) | ||||
Key Molecule: Serine/threonine-protein kinase ULK1 (ULK1) | [20] | |||
Molecule Alteration | Expression | Down-regulation |
||
Sensitive Disease | Lung cancer [ICD-11: 2C25.5] | |||
Experimental Note | Revealed Based on the Cell Line Data | |||
Cell Pathway Regulation | Cell apoptosis | Activation | hsa04210 | |
miR106a/ULk1 signaling pathway | Inhibition | hsa05206 | ||
In Vitro Model | A549 cells | Lung | Homo sapiens (Human) | CVCL_0023 |
H460 cells | Lung | Homo sapiens (Human) | CVCL_0459 | |
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. |
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] | |||
Molecule Alteration | Missense mutation | p.E711K |
||
Resistant Disease | HER2 positive breast cancer [ICD-11: 2C60.8] | |||
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
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