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
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Indication
In total 2 Indication(s)
Myeloproliferative neoplasm [ICD-11: 2A22]
Approved
[1]
Multiple myeloma [ICD-11: 2A83]
Phase 2
[1]
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]
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]
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
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
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Chronic myeloid leukemia [ICD-11: 2A20]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [4], [5], [6]
Molecule Alteration Missense mutation
p.F317L
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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) Click to Show/Hide
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) Click to Show/Hide
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) Click to Show/Hide
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) Click to Show/Hide
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]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
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]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
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]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
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) Click to Show/Hide
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) Click to Show/Hide
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) Click to Show/Hide
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]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
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
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 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 10 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 11 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 12 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 13 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 14 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 15 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 16 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 17 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 18 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 19 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.
Ref 20 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.

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