Drug Information

Drug (ID: DG00144) and It's Reported Resistant Information

• Name: Imatinib
• Synonyms: Cgp 57148; Glamox; Glamox (TN); Gleevec (TN); Glivec (TN); Imatinib (INN); Imatinib (STI571); Imatinib Methansulfonate; Imatinib [INN:BAN]; 112GI019; 152459-95-5; BKJ8M8G5HI; CCRIS 9076; CGP-57148; CHEMBL941; Imatinib free base; STI; UNII-BKJ8M8G5HI
• Indication:
  In total 5 Indication(s)
  Mature B-cell lymphoma [ICD-11: 2A85]; Approved; [1]
  Myeloproliferative neoplasm [ICD-11: 2A22]; Approved; [1]
  Malignant intestine neoplasm [ICD-11: 2C0Z]; Phase 3; [1]
  Lung cancer [ICD-11: 2C25]; Phase 2; [1]
  Mastocytosis [ICD-11: 2A21]; Investigative; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (9 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  Atypical chronic myeloid leukemia [ICD-11: 2A41]; [3]
  Brain cancer [ICD-11: 2A00]; [4]
  Breast cancer [ICD-11: 2C60]; [5]
  Chronic myeloid leukemia [ICD-11: 2A20]; [2], [6], [7]
  Dermatofibrosarcoma protuberans [ICD-11: 2B53]; [8]
  Gastrointestinal cancer [ICD-11: 2B5B]; [9], [10], [11]
  Kidney cancer [ICD-11: 2C90]; [12]
  Metastatic liver cancer [ICD-11: 2D80]; [13]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Chronic myeloid leukemia [ICD-11: 2A20]; [14]
  Gastrointestinal cancer [ICD-11: 2B5B]; [15]
• Target: Fusion protein Bcr-Abl (Bcr-Abl); BCR_HUMAN-ABL1_HUMAN; [1]
• Target: Mcl-1 messenger RNA (MCL-1 mRNA); MCL1_HUMAN; [1]
• Target: Platelet-derived growth factor receptor (PDGFR); NOUNIPROTAC; [1]
• Target: Tyrosine-protein kinase Kit (KIT); KIT_HUMAN; [1]
• Formula: C29H31N7O
• IsoSMILES: CC1=C(C=C(C=C1)NC(=O)C2=CC=C(C=C2)CN3CCN(CC3)C)NC4=NC=CC(=N4)C5=CN=CC=C5
• InChI: 1S/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34)
• InChIKey: KTUFNOKKBVMGRW-UHFFFAOYSA-N
• PubChem CID: 5291
• ChEBI ID: CHEBI:45783
• TTD Drug ID: D0AZ3C
• VARIDT ID: DR00032
• DrugBank ID: DB00619

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-203 [4]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: SNAI2 is a direct target of miR-203 and that miR-203-mediated inhibition of SNAI2 is dependent on a conversed motif in the 3'-UTR of SNAI2. Recent independent studies have shown that overexpression of SNAI2 alters cell invasion, motility, chemoresistance, metastasis and poor prognosis in several human cancers. As a member of the snail family of transcription factors, SNAI2 can repress E-cadherin transcription and induce EMT directly. Therefore, SNAI2 overexpression due to reduction of miR-203 may result in EMT and chemoresistance in GBM via these pathways. Additionally, miR-203 may relieve E-cadherin from transcriptional repression by targeting SNAI2 signaling. Nevertheless, because one single miRNA might have multiple targets, judicious considerations are essential for identi cation of the main functional targets.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger protein SNAI2 (SNAI2) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: SNAI2 is a direct target of miR-203 and that miR-203-mediated inhibition of SNAI2 is dependent on a conversed motif in the 3'-UTR of SNAI2. Recent independent studies have shown that overexpression of SNAI2 alters cell invasion, motility, chemoresistance, metastasis and poor prognosis in several human cancers. As a member of the snail family of transcription factors, SNAI2 can repress E-cadherin transcription and induce EMT directly. Therefore, SNAI2 overexpression due to reduction of miR-203 may result in EMT and chemoresistance in GBM via these pathways. Additionally, miR-203 may relieve E-cadherin from transcriptional repression by targeting SNAI2 signaling. Nevertheless, because one single miRNA might have multiple targets, judicious considerations are essential for identi cation of the main functional targets.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-296-3p [16]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Potassium voltage-gated channel subfamily H member 1 (KCNH1) [16]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [17]

• Molecule Alteration: Missense mutation; p.Y253H+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
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [17]

• Molecule Alteration: Missense mutation; p.T315I+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
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [17]

• Molecule Alteration: Missense mutation; p.P480L
• 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: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [17]

• Molecule Alteration: Missense mutation; p.M244V+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
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [7], [18]

• Molecule Alteration: Missense mutation; p.G250E
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.F359V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [19], [20], [21]

• Molecule Alteration: Missense mutation; p.E459K
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [17]

• Molecule Alteration: Missense mutation; p.E450K
• 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: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [17]

• Molecule Alteration: Missense mutation; p.E255K+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
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [2], [6], [7]

• Molecule Alteration: Missense mutation; p.E255K
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

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

• Molecule Alteration: Missense mutation; p.Y320C
• 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: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [22], [23], [24]

• 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
• Experiment for Drug Resistance: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

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

• Molecule Alteration: Missense mutation; p.V256L
• 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: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [22], [25]

• Molecule Alteration: Missense mutation; p.T277A
• 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: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

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

• Molecule Alteration: Missense mutation; p.S438C
• 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: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

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

• Molecule Alteration: Missense mutation; p.M351K
• 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: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

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

• Molecule Alteration: Missense mutation; p.K378R
• 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: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

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

• Molecule Alteration: Missense mutation; p.E494G
• 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: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [22], [26], [27]

• Molecule Alteration: Missense mutation; p.E450G
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.E355G
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

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

• Molecule Alteration: Missense mutation; p.A399T
• 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: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. In elderly patients, the presence of a mutation at the time of imatinib failure is associated with a worse response to dasatinib therapy.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [28]

• Molecule Alteration: Missense mutation; p.N368S
• 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: Denaturing high performance liquid chromatography (dHPLC) assay; Direct DNA sequencing method assay
• Experiment for Drug Resistance: Overall survival assay
• Mechanism Description: Fifteen different types of mutations (T315I, E255k, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [28]

• Molecule Alteration: Missense mutation; p.G251E
• 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: Denaturing high performance liquid chromatography (dHPLC) assay; Direct DNA sequencing method assay
• Experiment for Drug Resistance: Overall survival assay
• Mechanism Description: Fifteen different types of mutations (T315I, E255k, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [28], [29], [30]

• Molecule Alteration: Missense mutation; p.A397P
• 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: Denaturing high performance liquid chromatography (dHPLC) assay; Direct DNA sequencing method assay
• Experiment for Drug Resistance: Overall survival assay
• Mechanism Description: Fifteen different types of mutations (T315I, E255k, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [31]

• 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) [31]

• 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) [31]

• 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) [21], [29], [30]

• Molecule Alteration: Missense mutation; p.L298V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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) [17], [21], [26]

• Molecule Alteration: Missense mutation; p.F317V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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) [31]

• 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) [31]

• 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) [31]

• 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) [32]

• Molecule Alteration: Missense mutation; p.Q252K
• 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: Next generation sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: HSCT is an important salvage option for TkI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [33]

• Molecule Alteration: Missense mutation; p.Q252M
• 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: Pyrosequencing analysis
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (kDMs).

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [33]

• Molecule Alteration: Missense mutation; p.P310S
• 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: Pyrosequencing analysis
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (kDMs).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [26], [33]

• Molecule Alteration: Missense mutation; p.H396P
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Pyrosequencing analysis
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (kDMs).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [7], [18]

• Molecule Alteration: Missense mutation; p.F311I
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: PCR-Invader assay; Direct sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: The PCR-Invader assay used in this study is an appropriate tool for the screening of mutations during TkI therapy. High Sokal score is only predictive factor for emergence of mutation in CML-CP. P-loop mutations were associated with poor PFS in CML-CP.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [34]

• Molecule Alteration: Missense mutation; p.Q252E
• 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: In late CP or advanced CML, ABL-kinase mutations occur as an intraclonal event in the primitive Ph1+ stem cell compartments with progression of this clone towards IM-resistant blast phase.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [35]

• Molecule Alteration: Structural mutation; Structural variation
• 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: ASO-PCR and sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutations in the kinase domain (kD) of BCR-ABL are the leading cause of acquired imatinib resistance.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [21], [26], [36]

• Molecule Alteration: Missense mutation; p.L364I
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Real-time Taqman assay; Direct sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Point mutation was the major mechanism of primary cytogenetic resistance to imatinib mesylate in the present study. Patients with mutations had inferior progression-free survival compared to those without mutations. Resistance is higher among patients with advanced CML. Point mutations in the ABL kinase domain and amplification of the BCR-ABL fusion gene have emerged as important mechanisms responsible for resistance to imatinib. Biochemical and cellular assays have demonstrated that different BCR-ABL mutations might result in varying levels of resistance.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [28], [37], [38]

• Molecule Alteration: Missense mutation; p.V289F
• 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: Overall survival assay
• Mechanism Description: Point mutations were detected in 36 of 154 patients by direct sequencing. In our series, the single most common mutations were G250E, E255k/V, and M351T. The presence of mutations correlated significantly with accelerated phase, lack of molecular response, and lower cytogenetic and hematological responses.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [23], [26], [39]

• 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: Sanger sequencing assay
• Mechanism Description: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [40]

• Molecule Alteration: Missense mutation; p.N374Y
• 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: Nested RT-PC assay; Gene sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Presence of mutations predicted for poorer responses and EFS to dose escalation. IM dose escalation is likely to be effective only in those harboring no or relatively sensitive kD mutations.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [41]

• Molecule Alteration: Missense mutation; p.E453G
• 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: Sanger sequencing assay
• Mechanism Description: The data suggest that some BCR-ABL1 mutations may persist at undetectable levels for many years after changing therapy, and can be reselected and confer resistance to subsequent inhibitors.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [41]

• Molecule Alteration: Missense mutation; p.E275K
• 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: Sanger sequencing assay
• Mechanism Description: The data suggest that some BCR-ABL1 mutations may persist at undetectable levels for many years after changing therapy, and can be reselected and confer resistance to subsequent inhibitors.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [25]

• Molecule Alteration: Missense mutation; p.L340L
• 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: The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with clonal cytogenetic evolution. The change to second-generation TkI can overcome imatinib resistance in most of the mutated patients.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [25]

• Molecule Alteration: Missense mutation; p.D276A
• 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: The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with clonal cytogenetic evolution. The change to second-generation TkI can overcome imatinib resistance in most of the mutated patients.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [19], [20], [21]

• Molecule Alteration: Missense mutation; p.I418V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: The most frequent mutant is M244V, followed by Y253H, F359C/V/I, G250E, E255k, and T315I. Only seven patients (9%) have T315I mutants, and all showed hematologic resistance. Three of them were in the ECP and three in the LCP. Look-back studies show that mutants were detected 0-20 (median 7) months ahead of the appearance of clinical resistance in 15 tested patients with acquired resistance.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [29]

• Molecule Alteration: Missense mutation; p.E453L
• 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: The most frequent mutant is M244V, followed by Y253H, F359C/V/I, G250E, E255k, and T315I. Only seven patients (9%) have T315I mutants, and all showed hematologic resistance. Three of them were in the ECP and three in the LCP. Look-back studies show that mutants were detected 0-20 (median 7) months ahead of the appearance of clinical resistance in 15 tested patients with acquired resistance.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [27], [29]

• Molecule Alteration: Missense mutation; p.E450A
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: The most frequent mutant is M244V, followed by Y253H, F359C/V/I, G250E, E255k, and T315I. Only seven patients (9%) have T315I mutants, and all showed hematologic resistance. Three of them were in the ECP and three in the LCP. Look-back studies show that mutants were detected 0-20 (median 7) months ahead of the appearance of clinical resistance in 15 tested patients with acquired resistance.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [29]

• Molecule Alteration: Missense mutation; p.E279Y
• 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: The most frequent mutant is M244V, followed by Y253H, F359C/V/I, G250E, E255k, and T315I. Only seven patients (9%) have T315I mutants, and all showed hematologic resistance. Three of them were in the ECP and three in the LCP. Look-back studies show that mutants were detected 0-20 (median 7) months ahead of the appearance of clinical resistance in 15 tested patients with acquired resistance.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [42]

• Molecule Alteration: Missense mutation; p.L387F
• 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: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [21], [26], [42]

• Molecule Alteration: Missense mutation; p.E459G
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [42]

• Molecule Alteration: Missense mutation; p.E453A
• 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: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [42]

• Molecule Alteration: Missense mutation; p.E279A
• 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: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [42]

• Molecule Alteration: Missense mutation; p.D276N
• 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: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [42]

• Molecule Alteration: Missense mutation; p.S438C
• 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: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [17], [19], [26]

• Molecule Alteration: Missense mutation; p.S417Y
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [26]

• Molecule Alteration: Missense mutation; p.G251D
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.F382L
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [21], [26]

• Molecule Alteration: Missense mutation; p.E453K
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [26]

• Molecule Alteration: Missense mutation; p.E453D
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [26]

• Molecule Alteration: Missense mutation; p.E352G
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [26]

• Molecule Alteration: Missense mutation; p.E352D
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [26]

• Molecule Alteration: Missense mutation; p.E282G
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [26]

• Molecule Alteration: Missense mutation; p.E279Z
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [26]

• Molecule Alteration: Missense mutation; p.D482V
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [43]

• Molecule Alteration: Missense mutation; p.K419E
• 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 confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 kD, since 40.0% of our CML patients who harbored a BCR-ABL1 kD mutation died from CML while receiving TkI treatment.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [43]

• Molecule Alteration: Missense mutation; p.E279K
• 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 confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 kD, since 40.0% of our CML patients who harbored a BCR-ABL1 kD mutation died from CML while receiving TkI treatment.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [7]

• Molecule Alteration: Missense mutation; p.Q252R
• 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 identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [7]

• Molecule Alteration: Missense mutation; p.M343T
• 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 identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [44]

• Molecule Alteration: Missense mutation; p.K294>RGG
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: BCR-ABL kinase domain mutations were sequentially analyzed in a patient with chronic myeloid leukemia (CML) who exhibited repeated B-lymphoid blast crisis (CML-BC) during treatment with imatinib and dasatinib. We first identified five mutant BCR-ABL clones: Y253H, G250E, F311L, F317L and k294RGG, which was generated by two-nucleotide mutations and six-nucleotide insertion, at the third BC during the imatinib treatment, and retrospectively found that three of them (Y253H, G250E, k294RGG) were already present at the second BC.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [31]

• 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) [31]

• 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) [31]

• 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.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [45]

• Molecule Alteration: Missense mutation; p.T315N
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: cDNA sequencing assay; Denaturing high-power liquid chromatography assay
• Mechanism Description: Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of kIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [45]

• Molecule Alteration: Missense mutation; p.F359A
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: cDNA sequencing assay; Denaturing high-power liquid chromatography assay
• Mechanism Description: Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of kIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [46]

• Molecule Alteration: Missense mutation; p.G398R
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Nested reverse transcriptase polymerase chain reaction assay; Direct sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Two patients had p.E355G mutation in the catalytic domain, and the third patient had p.G398R in the activation loop that is reported here for the first time. Mutation status had no impact on the overall survival and progression-free survival. p.E355G mutation was correlated with shorter survival (P=0.047) in resistant patients. We conclude that BCR- ABL1 mutations are associated with the clinical resistance, but may not be considered the only cause of resistance to imatinib. Mutational analysis may identify resistant patients at risk of disease progression.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.Y253H
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Allele-specific (AS)-RT-PCR assay
• Mechanism Description: We herein describe the development of a rapid allele-specific (AS)-RT-PCR assay to identify the T315I mutation, which confers full resistance to all available tyrosine-kinase inhibitors (TkI).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [7], [18]

• Molecule Alteration: Missense mutation; p.T315I
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay; Allele-specific (AS)-RT-PCR assay
• Mechanism Description: We herein describe the development of a rapid allele-specific (AS)-RT-PCR assay to identify the T315I mutation, which confers full resistance to all available tyrosine-kinase inhibitors (TkI).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.Y253F
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.Q252H
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [21], [26], [47]

• Molecule Alteration: Missense mutation; p.M388L
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [7], [18]

• Molecule Alteration: Missense mutation; p.M351T
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.M244V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.L387M
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [7], [18], [19]

• Molecule Alteration: Missense mutation; p.H396R
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [21]

• Molecule Alteration: Missense mutation; p.E459Q
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [21], [28]

• Molecule Alteration: Missense mutation; p.E355A
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [18], [19], [45]

• Molecule Alteration: Missense mutation; p.E255V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [21], [29], [39]

• Molecule Alteration: Missense mutation; p.D276G
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [21], [32]

• Molecule Alteration: Missense mutation; p.A433T
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-328 [48]

• Molecule Alteration: Expression; Down-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 Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA MALAT1 promotes cell proliferation and imatinib resistance by suppressing miR-328 in chronic myelogenous leukemia.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [48]

• 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 Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA MALAT1 promotes cell proliferation and imatinib resistance by suppressing miR-328 in chronic myelogenous leukemia.

Key Molecule: hsa_circ_BA9.3 [49]

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

Key Molecule: hsa-miR-205-5p [50]

• 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: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCC2 was a downstream target of miR205-5p, overexpression of miR205-5p suppressed the expression of ABCC2 in k562-R cells. SNHG5 promotes imatinib resistance through upregulating ABCC2. SNHG5 promotes imatinib resistance in CML via acting as a competing endogenous RNA against miR205-5p.

Key Molecule: Small nucleolar RNA host gene 5 (SNHG5) [50]

• 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: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: SNHG5 promotes imatinib resistance through upregulating ABCC2 and promotes imatinib resistance in CML via acting as a competing endogenous RNA against miR205-5p.

Key Molecule: hsa-miR-29a-3p [51]

• 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.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR29a-3p observed in CML LSCs led to the down-regulation of its target TET2 and conferred TkI-resistance to CML LSCs in vitro.

Key Molecule: hsa-miR-494-3p [51]

• 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.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: miR494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TkI-induced apoptosis.

Key Molecule: hsa-miR-660-5p [51]

• 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.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR660-5p observed in CML LSCs led to the down-regulation of its target EPAS1 and conferred TkI-resistance to CML LSCs in vitro.

Key Molecule: hsa-let-7i [52]

• 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: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometric analysis; CFU assay
• Mechanism Description: miR224 and let-7i regulate the proliferation and chemosensitivity of CML cells probably via targeting ST3GAL IV.

Key Molecule: hsa-mir-224 [52]

• 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: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometric analysis; CFU assay
• Mechanism Description: miR224 and let-7i regulate the proliferation and chemosensitivity of CML cells probably via targeting ST3GAL IV.

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [53]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA HULC promotes cell proliferation by regulating PI3k/AkT signaling pathway in chronic myeloid leukemia. HULC aggrevates CML by regulating PI3k/AkT. Inhibition of HULC enhances imatinib induced CML apoptosis. 3. HULC increased c-Myc and Bcl-2 by sequestering miR200a-3p.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [54]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562-R cells; Pleural effusion; Homo sapiens (Human); CVCL_5950
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Annexin V/propidium iodide staining assay
• Mechanism Description: Knockdown of HOTAIR expression downregulated the MRP1 expression levels in the k562-imatinib cells and resulted in higher sensitivity to the imatinib treatment. In addition, the activation of PI3k/Akt was greatly attenuated when HOTAIR was knocked down in k562-imatinib cells.

Key Molecule: hsa-mir-16 [55]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA UCA1 Contributes to Imatinib Resistance by Acting as a ceRNA Against miR16 in Chronic Myeloid Leukemia Cells. UCA1 directly interacts with miR16.

Key Molecule: Urothelial cancer associated 1 (UCA1) [55]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: UCA1 functions as a ceRNA of MDR1, UCA1 promotes IM resistance of CML cell through regulation of MDR1. Ectopic expression of MDR1 or silence of miR16 partially rescued this suppression induced by UCA1 knockdown.

Key Molecule: hsa-miR-486-5p [14]

• 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 Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-486-5p expression contributes to survival of BCR-ABL-transformed cells after imatinib treatment and that inhibition of miR-486-5p enhances the sensitivity of CML progenitors to imatinib-mediated apoptosis.

Key Molecule: hsa-mir-199b [56]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: RT-PCR was found to be a more sensitive technique to study miRNA expression in 9q deleted patients where deletions are missed out by FISH. The miRNA expression is important in the 9q deleted patients as miR-199b associated with drug resistance and can be used as a prognostic factor in 9q deleted CML patients.

Key Molecule: hsa-mir-181c [57]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Response evaluation criteria in solid tumors assay
• Mechanism Description: Significant down-regulation of miR-181c in imatinib-resistant versus imatinib-responders was confirmed by qRT-PCR. Some miR-181c target genes such as PBX3, HSP90B1, NMT2 and RAD21 have been associated with drug response.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [23]

• 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.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [50]

• 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: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCC2 was a downstream target of miR205-5p, overexpression of miR205-5p suppressed the expression of ABCC2 in k562-R cells. SNHG5 promotes imatinib resistance through upregulating ABCC2. SNHG5 promotes imatinib resistance in CML via acting as a competing endogenous RNA against miR205-5p.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [54]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562-R cells; Pleural effusion; Homo sapiens (Human); CVCL_5950
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Annexin V/propidium iodide staining assay
• Mechanism Description: Knockdown of HOTAIR expression downregulated the MRP1 expression levels in the k562-imatinib cells and resulted in higher sensitivity to the imatinib treatment. In addition, the activation of PI3k/Akt was greatly attenuated when HOTAIR was knocked down in k562-imatinib cells.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [55]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: UCA1 functions as a ceRNA of MDR1, UCA1 promotes IM resistance of CML cell through regulation of MDR1. Ectopic expression of MDR1 or silence of miR16 partially rescued this suppression induced by UCA1 knockdown.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [49]

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

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [49]

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

Key Molecule: Myc proto-oncogene protein (MYC) [51]

• 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.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: miR494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TkI-induced apoptosis.

Key Molecule: Hypoxia-inducible factor 2-alpha (EPAS1) [51]

• 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.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR660-5p observed in CML LSCs led to the down-regulation of its target EPAS1 and conferred TkI-resistance to CML LSCs in vitro.

Key Molecule: Methylcytosine dioxygenase TET2 (TET2) [51]

• 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.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR29a-3p observed in CML LSCs led to the down-regulation of its target TET2 and conferred TkI-resistance to CML LSCs in vitro.

Key Molecule: Sialyltransferase 4C (SIAT4C) [52]

• 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: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometric analysis; CFU assay
• Mechanism Description: miR224 and let-7i regulate the proliferation and chemosensitivity of CML cells probably via targeting ST3GAL IV.

Key Molecule: Myc proto-oncogene protein (MYC) [53]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA HULC promotes cell proliferation by regulating PI3k/AkT signaling pathway in chronic myeloid leukemia. HULC aggrevates CML by regulating PI3k/AkT. Inhibition of HULC enhances imatinib induced CML apoptosis. 3. HULC increased c-Myc and Bcl-2 by sequestering miR200a-3p.

Key Molecule: NUP98-DDX10 fusion protein type 1 (NUP98-DDX10 ) [58]

• Molecule Alteration: Structural mutation; Structural variation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: RT-PCR analysis
• Experiment for Drug Resistance: Western blot analysis with anti-CrkL antibody assay
• Mechanism Description: Collectively, these observations raise the possibility that NUP98/DDX10 might have played a role not only in disease progression but also in the acquisition of resistance to imatinib.

Key Molecule: GTPase Nras (NRAS) [59], [60]

• 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
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [26]

• Molecule Alteration: Missense mutation; p.R328M
• 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: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-7 [61]

• 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: BCR-ABL/PI3K/AKT signaling pathway; Inhibition; hsa05220
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR7 inhibits cell proliferation and increases cell apoptosis in k562 cells and downregulates BCR-ABL/PI3k/AkT signaling in k562 cells, thus sensitizing k562 cells to imatinib.

Key Molecule: Maternally expressed 3 (MEG3) [62]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC/PI Apoptosis Detection assay
• Mechanism Description: LncRNA MEG3 Regulates Imatinib Resistance in Chronic Myeloid Leukemia via Suppressing microRNA-21. MEG3 and miR21 were negatively correlated in CML patients, miR21 mimics reversed the phenotype of MEG3-overexpression in imatinib-resistant k562 cells.

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [63]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The c-Myc-regulated LncRNA NEAT1 and paraspeckles modulate imatinib-induced apoptosis in CML cells.

Key Molecule: hsa-miR-199a-5p [64]

• 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 Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt2-mediated Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells.

Key Molecule: hsa-miR-199b-5p [64]

• 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 Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt2-mediated Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells.

Key Molecule: hsa-mir-202 [65]

• 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 viability; Activation; hsa05200
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: EM2 cells; Bone; Homo sapiens (Human); CVCL_1196
• In Vitro Model: EM3 cells; Bone; Homo sapiens (Human); CVCL_2033
• In Vitro Model: LAMA 84 cells; Bone; Homo sapiens (Human); CVCL_0388
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU assay; Caspase-3 assay
• Mechanism Description: Overexpression of miR-202 sensitized imatinib resistant CML through the miR-202-mediated glycolysis inhibition by targetting Hk2.

Key Molecule: hsa-mir-1301 [66]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-1301-mediated RanGAP1 downregulation induces BCR-ABL nuclear entrapment to enhance imatinib efficacy in chronic myeloid leukemia cells.

Key Molecule: hsa-mir-130a [67]

• 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 Pathway Regulation: p53 signaling pathway; Regulation; hsa04115
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: BCL-2, MCL-1 and XIAP were the target genes of miR-130a. BCL-2, MCL-1, TCL-1 and XIAP protein levels were significantly higher in patients with drug-sensitive CML cells. Transfected miR-130a mimics significantly decreased the protein expression of BCL-1, MCL-1 and XIAP. Transfected miR-130a significantly increased the CML sensitivity to Gleevec.

Key Molecule: hsa-mir-30e [68]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JAKT/STAT/PI3K/AKT signaling pathway; Inhibition; hsa04630
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Meg-01 cells; Blood; Homo sapiens (Human); CVCL_0425
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Luciferase assay verified that miR-30e directly targets ABL. Enforced expression of miR-30e in k562 cells suppressed proliferation and induced apoptosis of these cells and sensitized them to imatinib treatment. These findings strongly suggest that miR-30e acts as a tumor suppressor by downregulating BCR-ABL expression.

Key Molecule: hsa-mir-30a [69], [70]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Intrinsic apoptotic signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a mimic or knockdown of autophagy genes (ATGs) such as Beclin 1 and ATG5 by short hairpin RNA enhances imatinib-induced cytotoxicity and promotes mitochondria-dependent intrinsic apoptosis. In contrast, knockdown of miR-30a by antagomiR-30a increases the expression of Beclin 1 and ATG5, and inhibits imatinib-induced cytotoxicity. And MIR30A mimics, as well as knockdown of BECN1 and ATG5, increases intrinsic apoptotic pathways.

Key Molecule: hsa-mir-203 [71]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: BaF3-BCR/ABLT315I cells; Bone marrow; Homo sapiens (Human); CVCL_UE64
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Interference BCR/ABL expression with miR-203 restored the sensitivity to imatinib in cells expressing the imatinib-resistant BCR/ABL kinase domain mutant T315I.

Key Molecule: hsa-mir-144 [72]

• 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 Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: c-Myc expression was upregulated in the imatinib resistant k562R cells, which in turn increased the expression of miR-144/451, restoration of miR-144/451 or knockdown of Myc could sensitize the imatinib resistant cells to apoptosis. Myc, miR-144/451 form a regulatory pathway and contribute to the imatinib resistance.

Key Molecule: hsa-mir-451 [72]

• 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 Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: c-Myc expression was upregulated in the imatinib resistant k562R cells, which in turn increased the expression of miR-144/451, restoration of miR-144/451 or knockdown of Myc could sensitize the imatinib resistant cells to apoptosis. Myc, miR-144/451 form a regulatory pathway and contribute to the imatinib resistance.

Key Molecule: hsa-mir-21 [62]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC/PI Apoptosis Detection assay
• Mechanism Description: LncRNA MEG3 regulates imatinib resistance in chronic myeloid leukemia via suppressing microRNA-21. MEG3 and miR21 were negatively correlated in CML patients, miR21 mimics reversed the phenotype of MEG3-overexpression in imatinib-resistant k562 cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [62]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC/PI Apoptosis Detection assay
• Mechanism Description: Overexpression of MEG3 in imatinib-resistant k562 cells markedly decreased cell proliferation, increased cell apoptosis, reversed imatinib resistance, and reduced the expression of MRP1, MDR1, and ABCG2.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [62]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC/PI Apoptosis Detection assay
• Mechanism Description: Overexpression of MEG3 in imatinib-resistant k562 cells markedly decreased cell proliferation, increased cell apoptosis, reversed imatinib resistance, and reduced the expression of MRP1, MDR1, and ABCG2.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [62]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC/PI Apoptosis Detection assay
• Mechanism Description: Overexpression of MEG3 in imatinib-resistant k562 cells markedly decreased cell proliferation, increased cell apoptosis, reversed imatinib resistance, and reduced the expression of MRP1, MDR1, and ABCG2.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [61]

• 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: BCR-ABL/PI3K/AKT signaling pathway; Inhibition; hsa05220
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR7 inhibits cell proliferation and increases cell apoptosis in k562 cells and downregulates BCR-ABL/PI3k/AkT signaling in k562 cells, thus sensitizing k562 cells to imatinib.

Key Molecule: Int-1-related protein (WNT2) [64]

• 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 Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt2-mediated Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells.

Key Molecule: Hexokinase-2 (HK2) [65]

• 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 viability; Activation; hsa05200
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: EM2 cells; Bone; Homo sapiens (Human); CVCL_1196
• In Vitro Model: EM3 cells; Bone; Homo sapiens (Human); CVCL_2033
• In Vitro Model: LAMA 84 cells; Bone; Homo sapiens (Human); CVCL_0388
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU assay; Caspase-3 assay
• Mechanism Description: Overexpression of miR-202 sensitized imatinib resistant CML through the miR-202-mediated glycolysis inhibition by targetting Hk2.

Key Molecule: Ran GTPase-activating protein 1 (RANGAP1) [66]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-1301-mediated RanGAP1 downregulation induces BCR-ABL nuclear entrapment to enhance imatinib efficacy in chronic myeloid leukemia cells.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [67]

• 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 Pathway Regulation: p53 signaling pathway; Regulation; hsa04115
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: BCL-2, MCL-1 and XIAP were the target genes of miR-130a. BCL-2, MCL-1, TCL-1 and XIAP protein levels were significantly higher in patients with drug-sensitive CML cells. Transfected miR-130a mimics significantly decreased the protein expression of BCL-1, MCL-1 and XIAP. Transfected miR-130a significantly increased the CML sensitivity to Gleevec.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [67]

• 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 Pathway Regulation: p53 signaling pathway; Regulation; hsa04115
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: BCL-2, MCL-1 and XIAP were the target genes of miR-130a. BCL-2, MCL-1, TCL-1 and XIAP protein levels were significantly higher in patients with drug-sensitive CML cells. Transfected miR-130a mimics significantly decreased the protein expression of BCL-1, MCL-1 and XIAP. Transfected miR-130a significantly increased the CML sensitivity to Gleevec.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [67]

• 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 Pathway Regulation: p53 signaling pathway; Regulation; hsa04115
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: BCL-2, MCL-1 and XIAP were the target genes of miR-130a. BCL-2, MCL-1, TCL-1 and XIAP protein levels were significantly higher in patients with drug-sensitive CML cells. Transfected miR-130a mimics significantly decreased the protein expression of BCL-1, MCL-1 and XIAP. Transfected miR-130a significantly increased the CML sensitivity to Gleevec.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [68]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JAKT/STAT/PI3K/AKT signaling pathway; Inhibition; hsa04630
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Meg-01 cells; Blood; Homo sapiens (Human); CVCL_0425
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Luciferase assay verified that miR-30e directly targets ABL. Enforced expression of miR-30e in k562 cells suppressed proliferation and induced apoptosis of these cells and sensitized them to imatinib treatment. These findings strongly suggest that miR-30e acts as a tumor suppressor by downregulating BCR-ABL expression.

Key Molecule: Autophagy protein 5 (ATG5) [69]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a mimic or knockdown of autophagy genes (ATGs) such as Beclin 1 and ATG5 by short hairpin RNA enhances imatinib-induced cytotoxicity and promotes mitochondria-dependent intrinsic apoptosis. In contrast, knockdown of miR-30a by antagomiR-30a increases the expression of Beclin 1 and ATG5, and inhibits imatinib-induced cytotoxicity.

Key Molecule: Beclin-1 (BECN1) [69]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a mimic or knockdown of autophagy genes (ATGs) such as Beclin 1 and ATG5 by short hairpin RNA enhances imatinib-induced cytotoxicity and promotes mitochondria-dependent intrinsic apoptosis. In contrast, knockdown of miR-30a by antagomiR-30a increases the expression of Beclin 1 and ATG5, and inhibits imatinib-induced cytotoxicity.

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]

• 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
• Mechanism Description: Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. In summary, binding of STI571 to BCR-ABL depends on a number of specific interactions within the ATPbinding site. Our results strongly suggest that a patient could be resistant to STI571 by acquisition of different individual point mutations within the ATP-binding pocket or activation loop of BCR-ABL, even though the number of mutations might be limited. This factor could make it difficult to overcome resistance to STI571 by use of alternative kinase inhibitors.

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

• Molecule Alteration: Missense mutation; p.E255V
• 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
• Mechanism Description: Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. In summary, binding of STI571 to BCR-ABL depends on a number of specific interactions within the ATPbinding site. Our results strongly suggest that a patient could be resistant to STI571 by acquisition of different individual point mutations within the ATP-binding pocket or activation loop of BCR-ABL, even though the number of mutations might be limited. This factor could make it difficult to overcome resistance to STI571 by use of alternative kinase inhibitors.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [73]

• Molecule Alteration: Missense mutation; p.G250E
• 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 Molecule Alteration: PCR-Invader assay; Direct sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: The PCR-Invader assay used in this study is an appropriate tool for the screening of mutations during TkI therapy. High Sokal score is only predictive factor for emergence of mutation in CML-CP. P-loop mutations were associated with poor PFS in CML-CP.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [45]

• 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 Molecule Alteration: cDNA sequencing assay; Denaturing high-power liquid chromatography assay
• Mechanism Description: Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of kIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [45]

• Molecule Alteration: Missense mutation; p.D276G
• 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 Molecule Alteration: cDNA sequencing assay; Denaturing high-power liquid chromatography assay
• Mechanism Description: Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of kIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [2], [6], [45]

• Molecule Alteration: Missense mutation; p.Y253H
• 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 Molecule Alteration: Direct sequencing assay
• Mechanism Description: Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph+ ALL) and imatinib resistance (defined as loss of established hematologic response). Three mutations (T315I, Y253H, and F317L present in 3, 1, and 1 patients, respectively) have a predicted role in abrogating imatinib binding to BCR/ABL, whereas 3 other mutations (E255k, G250E, and M351T, present in 4, 2, and 2 patients, respectively) do not. Thus we confirm a high frequency of mutations clustered within the ATP-binding region of BCR/ABL in resistant patients.

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

• 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 Molecule Alteration: Direct sequencing assay
• Mechanism Description: Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph+ ALL) and imatinib resistance (defined as loss of established hematologic response). Three mutations (T315I, Y253H, and F317L present in 3, 1, and 1 patients, respectively) have a predicted role in abrogating imatinib binding to BCR/ABL, whereas 3 other mutations (E255k, G250E, and M351T, present in 4, 2, and 2 patients, respectively) do not. Thus we confirm a high frequency of mutations clustered within the ATP-binding region of BCR/ABL in resistant patients.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [74]

• Molecule Alteration: Missense mutation; p.M244V
• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: CR-Abl sequencing assay
• Experiment for Drug Resistance: Event-free survival assay
• Mechanism Description: M244V and H396 mutations have been shown to be more resistant to imatinib but both have been shown to be sensitive to second generation TkI's such as nilotinib and dasatinib.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [2], [74]

• Molecule Alteration: Missense mutation; p.H396P
• 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 Molecule Alteration: CR-Abl sequencing assay
• Experiment for Drug Resistance: Event-free survival assay
• Mechanism Description: M244V and H396 mutations have been shown to be more resistant to imatinib but both have been shown to be sensitive to second generation TkI's such as nilotinib and dasatinib.

Dermatofibrosarcoma protuberans [ICD-11: 2B53]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Caspase recruitment domain family member 10 (CARD10) [8]

• Molecule Alteration: Missense mutation; chr22:37891880C>G+chr22:37891912C>G
• Resistant Disease: Dermatofibrosarcoma protuberans [ICD-11: 2B53.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: Dermatofibrosarcoma protuberans tissue; N.A.
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: This finding includes mutations in the CARD10, PPP1R39, SAFB2, and STARD9 genes. CARD10 is associated with the activation of the NK-kB signaling pathway and is known to have clinical implications in gastric cancer, colon cancer, and non-small cell lung cance. A potential role for changes in the PPP1R39 gene has also been suggested in the development of human cancers. Further, the SAFB2 gene product is involved in a variety of cellular process, such as cell growth, apoptosis, and stress response and is associated with breast tumorigenesis. In a recent in vitro study, the STARD9 gene product was shown to be associated with mitotic microtubule formation and cell division and might be a potential candidate target to extend the reach of cancer therapeutics. Among the studies mentioned above, Crone et al. demonstrated that targeting CARD10 by microRNA-146a inhibited NF-kB signaling pathway activation in gastric cancer cell lines via reduction of tumor-promoting cytokines and growth factors including PDGFRB. This study showed the possible association between CARD10 inhibition and decreased level of PDGFR and also implied CARD10 activating mutation may be one of the possible resistance mechanism to PBGFR inhibition by imatinib in DFSP.

Key Molecule: ArfGAP with coiled-coil, ankyrin repeat and PH domains 2 (ACAP2) [8]

• Molecule Alteration: Missense mutation; chr3:195041480C>T
• Resistant Disease: Dermatofibrosarcoma protuberans [ICD-11: 2B53.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Dermatofibrosarcoma protuberans tissue; N.A.
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: This finding includes mutations in the CARD10, PPP1R39, SAFB2, and STARD9 genes. CARD10 is associated with the activation of the NK-kB signaling pathway and is known to have clinical implications in gastric cancer, colon cancer, and non-small cell lung cance. A potential role for changes in the PPP1R39 gene has also been suggested in the development of human cancers. Further, the SAFB2 gene product is involved in a variety of cellular process, such as cell growth, apoptosis, and stress response and is associated with breast tumorigenesis. In a recent in vitro study, the STARD9 gene product was shown to be associated with mitotic microtubule formation and cell division and might be a potential candidate target to extend the reach of cancer therapeutics. Among the studies mentioned above, Crone et al. demonstrated that targeting CARD10 by microRNA-146a inhibited NF-kB signaling pathway activation in gastric cancer cell lines via reduction of tumor-promoting cytokines and growth factors including PDGFRB. This study showed the possible association between CARD10 inhibition and decreased level of PDGFR and also implied CARD10 activating mutation may be one of the possible resistance mechanism to PBGFR inhibition by imatinib in DFSP.

Key Molecule: Katanin interacting protein (KATNIP) [8]

• Molecule Alteration: Missense mutation; chr16:27788348G>T
• Resistant Disease: Dermatofibrosarcoma protuberans [ICD-11: 2B53.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Dermatofibrosarcoma protuberans tissue; N.A.
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: This finding includes mutations in the CARD10, PPP1R39, SAFB2, and STARD9 genes. CARD10 is associated with the activation of the NK-kB signaling pathway and is known to have clinical implications in gastric cancer, colon cancer, and non-small cell lung cance. A potential role for changes in the PPP1R39 gene has also been suggested in the development of human cancers. Further, the SAFB2 gene product is involved in a variety of cellular process, such as cell growth, apoptosis, and stress response and is associated with breast tumorigenesis. In a recent in vitro study, the STARD9 gene product was shown to be associated with mitotic microtubule formation and cell division and might be a potential candidate target to extend the reach of cancer therapeutics. Among the studies mentioned above, Crone et al. demonstrated that targeting CARD10 by microRNA-146a inhibited NF-kB signaling pathway activation in gastric cancer cell lines via reduction of tumor-promoting cytokines and growth factors including PDGFRB. This study showed the possible association between CARD10 inhibition and decreased level of PDGFR and also implied CARD10 activating mutation may be one of the possible resistance mechanism to PBGFR inhibition by imatinib in DFSP.

Key Molecule: PAAQR7 (PAAQR7) [8]

• Molecule Alteration: Missense mutation; chr1:26190151G>T
• Resistant Disease: Dermatofibrosarcoma protuberans [ICD-11: 2B53.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Dermatofibrosarcoma protuberans tissue; N.A.
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: This finding includes mutations in the CARD10, PPP1R39, SAFB2, and STARD9 genes. CARD10 is associated with the activation of the NK-kB signaling pathway and is known to have clinical implications in gastric cancer, colon cancer, and non-small cell lung cance. A potential role for changes in the PPP1R39 gene has also been suggested in the development of human cancers. Further, the SAFB2 gene product is involved in a variety of cellular process, such as cell growth, apoptosis, and stress response and is associated with breast tumorigenesis. In a recent in vitro study, the STARD9 gene product was shown to be associated with mitotic microtubule formation and cell division and might be a potential candidate target to extend the reach of cancer therapeutics. Among the studies mentioned above, Crone et al. demonstrated that targeting CARD10 by microRNA-146a inhibited NF-kB signaling pathway activation in gastric cancer cell lines via reduction of tumor-promoting cytokines and growth factors including PDGFRB. This study showed the possible association between CARD10 inhibition and decreased level of PDGFR and also implied CARD10 activating mutation may be one of the possible resistance mechanism to PBGFR inhibition by imatinib in DFSP.

Key Molecule: SH3 domain containing ring finger 2 (SH3RF2) [8]

• Molecule Alteration: Missense mutation; chr5:145435750G>A
• Resistant Disease: Dermatofibrosarcoma protuberans [ICD-11: 2B53.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Dermatofibrosarcoma protuberans tissue; N.A.
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: This finding includes mutations in the CARD10, PPP1R39, SAFB2, and STARD9 genes. CARD10 is associated with the activation of the NK-kB signaling pathway and is known to have clinical implications in gastric cancer, colon cancer, and non-small cell lung cance. A potential role for changes in the PPP1R39 gene has also been suggested in the development of human cancers. Further, the SAFB2 gene product is involved in a variety of cellular process, such as cell growth, apoptosis, and stress response and is associated with breast tumorigenesis. In a recent in vitro study, the STARD9 gene product was shown to be associated with mitotic microtubule formation and cell division and might be a potential candidate target to extend the reach of cancer therapeutics. Among the studies mentioned above, Crone et al. demonstrated that targeting CARD10 by microRNA-146a inhibited NF-kB signaling pathway activation in gastric cancer cell lines via reduction of tumor-promoting cytokines and growth factors including PDGFRB. This study showed the possible association between CARD10 inhibition and decreased level of PDGFR and also implied CARD10 activating mutation may be one of the possible resistance mechanism to PBGFR inhibition by imatinib in DFSP.

Key Molecule: Scaffold attachment factor B2 (SAFB2) [8]

• Molecule Alteration: Missense mutation; chr19:5587776C>T
• Resistant Disease: Dermatofibrosarcoma protuberans [ICD-11: 2B53.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Dermatofibrosarcoma protuberans tissue; N.A.
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: This finding includes mutations in the CARD10, PPP1R39, SAFB2, and STARD9 genes. CARD10 is associated with the activation of the NK-kB signaling pathway and is known to have clinical implications in gastric cancer, colon cancer, and non-small cell lung cance. A potential role for changes in the PPP1R39 gene has also been suggested in the development of human cancers. Further, the SAFB2 gene product is involved in a variety of cellular process, such as cell growth, apoptosis, and stress response and is associated with breast tumorigenesis. In a recent in vitro study, the STARD9 gene product was shown to be associated with mitotic microtubule formation and cell division and might be a potential candidate target to extend the reach of cancer therapeutics. Among the studies mentioned above, Crone et al. demonstrated that targeting CARD10 by microRNA-146a inhibited NF-kB signaling pathway activation in gastric cancer cell lines via reduction of tumor-promoting cytokines and growth factors including PDGFRB. This study showed the possible association between CARD10 inhibition and decreased level of PDGFR and also implied CARD10 activating mutation may be one of the possible resistance mechanism to PBGFR inhibition by imatinib in DFSP.

Key Molecule: StAR related lipid transfer domain containing 9 (STARD9) [8]

• Molecule Alteration: Missense mutation; chr15:42984506G>A
• Resistant Disease: Dermatofibrosarcoma protuberans [ICD-11: 2B53.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Dermatofibrosarcoma protuberans tissue; N.A.
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: This finding includes mutations in the CARD10, PPP1R39, SAFB2, and STARD9 genes. CARD10 is associated with the activation of the NK-kB signaling pathway and is known to have clinical implications in gastric cancer, colon cancer, and non-small cell lung cance. A potential role for changes in the PPP1R39 gene has also been suggested in the development of human cancers. Further, the SAFB2 gene product is involved in a variety of cellular process, such as cell growth, apoptosis, and stress response and is associated with breast tumorigenesis. In a recent in vitro study, the STARD9 gene product was shown to be associated with mitotic microtubule formation and cell division and might be a potential candidate target to extend the reach of cancer therapeutics. Among the studies mentioned above, Crone et al. demonstrated that targeting CARD10 by microRNA-146a inhibited NF-kB signaling pathway activation in gastric cancer cell lines via reduction of tumor-promoting cytokines and growth factors including PDGFRB. This study showed the possible association between CARD10 inhibition and decreased level of PDGFR and also implied CARD10 activating mutation may be one of the possible resistance mechanism to PBGFR inhibition by imatinib in DFSP.

Key Molecule: Zinc finger FYVE-type containing 9 (ZFYVE9) [8]

• Molecule Alteration: Missense mutation; chr1:52704185G>T
• Resistant Disease: Dermatofibrosarcoma protuberans [ICD-11: 2B53.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Dermatofibrosarcoma protuberans tissue; N.A.
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: This finding includes mutations in the CARD10, PPP1R39, SAFB2, and STARD9 genes. CARD10 is associated with the activation of the NK-kB signaling pathway and is known to have clinical implications in gastric cancer, colon cancer, and non-small cell lung cance. A potential role for changes in the PPP1R39 gene has also been suggested in the development of human cancers. Further, the SAFB2 gene product is involved in a variety of cellular process, such as cell growth, apoptosis, and stress response and is associated with breast tumorigenesis. In a recent in vitro study, the STARD9 gene product was shown to be associated with mitotic microtubule formation and cell division and might be a potential candidate target to extend the reach of cancer therapeutics. Among the studies mentioned above, Crone et al. demonstrated that targeting CARD10 by microRNA-146a inhibited NF-kB signaling pathway activation in gastric cancer cell lines via reduction of tumor-promoting cytokines and growth factors including PDGFRB. This study showed the possible association between CARD10 inhibition and decreased level of PDGFR and also implied CARD10 activating mutation may be one of the possible resistance mechanism to PBGFR inhibition by imatinib in DFSP.

Gastrointestinal cancer [ICD-11: 2B5B]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [75], [76], [77]

• Molecule Alteration: Missense mutation; p.D820Y
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: KIT and PDGFRA mutation analysis was performed in the primary tumors of 27 patients. Of these, 17 tumors (63%) had primary mutations in kIT exon 11, 4 (15%) had primary mutations in kIT exon 9 mutation, and 6 (22%) wild-type kIT. PDGFRA mutations were not detected in any tumor. After surgery following imatinib treatment, mutation analysis was performed on the responsive and progressive lesions of 17 patients. In addition to the original mutation, one of two patients with FP harbored secondary mutation in kIT exon 17 in the progressive lesion, whereas the second patient had only the original mutation in the progressive lesion. In the five GP patients evaluated, all except one harbored a synchronous secondary mutation in kIT exon 17 in progressive lesions. Surprisingly, one patient harbored a synchronous secondary mutation in kIT exon 17, showing that kIT mutations were present in two different codons of exon 17 in five different progressive lesions. Responsive lesions, however, possessed only their original mutations.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [76], [77]

• Molecule Alteration: Missense mutation; p.D816E
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: KIT and PDGFRA mutation analysis was performed in the primary tumors of 27 patients. Of these, 17 tumors (63%) had primary mutations in kIT exon 11, 4 (15%) had primary mutations in kIT exon 9 mutation, and 6 (22%) wild-type kIT. PDGFRA mutations were not detected in any tumor. After surgery following imatinib treatment, mutation analysis was performed on the responsive and progressive lesions of 17 patients. In addition to the original mutation, one of two patients with FP harbored secondary mutation in kIT exon 17 in the progressive lesion, whereas the second patient had only the original mutation in the progressive lesion. In the five GP patients evaluated, all except one harbored a synchronous secondary mutation in kIT exon 17 in progressive lesions. Surprisingly, one patient harbored a synchronous secondary mutation in kIT exon 17, showing that kIT mutations were present in two different codons of exon 17 in five different progressive lesions. Responsive lesions, however, possessed only their original mutations.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [76], [78]

• Molecule Alteration: Missense mutation; p.T670E
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing assay
• Experiment for Drug Resistance: Magnetic resonance tomograph assay; Computer-assisted tomography assay
• Mechanism Description: Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired kIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [76]

• Molecule Alteration: Missense mutation; p.S709F
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing assay
• Experiment for Drug Resistance: Magnetic resonance tomograph assay; Computer-assisted tomography assay
• Mechanism Description: Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired kIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [79]

• Molecule Alteration: Missense mutation; p.D816A
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: PFS and OS were longer for patients with secondary kIT exon 13 or 14 mutations (which involve the kIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the kIT activation loop). Biochemical profiling studies confirmed the clinical results. The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [79], [80], [81]

• Molecule Alteration: Missense mutation; p.A829P
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: PFS and OS were longer for patients with secondary kIT exon 13 or 14 mutations (which involve the kIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the kIT activation loop). Biochemical profiling studies confirmed the clinical results. The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [82]

• Molecule Alteration: Missense mutation; p.D816H
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: While tyrosine ki.se inhibitors have been previously utilized for kIT-altered malig.ncies, this patient's specific mutation (D816H) has been shown to be resistant to both imatinib and sunitinib.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [78]

• Molecule Alteration: Missense mutation; p.Y578C
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [78]

• Molecule Alteration: Frameshift mutation; p.V569_Y578del
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [78]

• Molecule Alteration: Missense mutation; p.N680K
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [78]

• Molecule Alteration: Missense mutation; p.K818_D820>N
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [78]

• Molecule Alteration: Frameshift mutation; p.D579del
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
• Mechanism Description: Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [83]

• Molecule Alteration: Missense mutation; p.D820V
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing assay; Exome sequencing assay; Microarray transcription analysis
• Experiment for Drug Resistance: Overall survival assay
• Mechanism Description: Sanger sequencing revealed that R8 harbored kIT D820Y and R9 had kIT D820V as secondary kIT mutations.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [84]

• Molecule Alteration: Missense mutation; p.S821F
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: We were able to identify primary kIT mutations in all plasma samples. Additional mutations, including kIT exon 17 S821F and PDGFRA exon 18 D842V, were detected in the patient-matched plasma samples during follow-up and appeared to result in decreased sensitivity to TkIs. Our results demonstrate an approach by which primary and secondary mutations are readily detected in blood-derived circulating tumor DNA from patients with GIST.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [11], [75], [76]

• Molecule Alteration: Missense mutation; p.T670I
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: In situ Cell Death Detection assay
• Mechanism Description: We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of kIT protein expression. We demonstrate downregulation of kIT transcription as an underlying mechanism for bortezomib-mediated inhibition of kIT expression. Collectively, our results show that inhibition of the proteasome using bortezomib can effectively kill imatinib-sensitive and imatinib-resistant GIST cells in vitro and provide a rationale to test the efficacy of bortezomib in GIST patients. Bortezomib has a dual mode of action against GIST cells involving upregulation of pro-apoptotic histone H2AX and downregulation of oncogenic kIT.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [11], [75], [76]

• Molecule Alteration: Missense mutation; p.V654A
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [75], [76], [85]

• Molecule Alteration: Missense mutation; p.Y823D
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [78], [80], [85]

• Molecule Alteration: Missense mutation; p.N822Y
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [11], [75], [76]

• Molecule Alteration: Missense mutation; p.N822K
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [76], [77], [85]

• Molecule Alteration: Missense mutation; p.D820G
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [85], [79]

• Molecule Alteration: Missense mutation; p.D820A
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [80], [85], [86]

• Molecule Alteration: Missense mutation; p.D816H
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [77], [85], [86]

• Molecule Alteration: Missense mutation; p.C809G
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• In Vitro Model: GIST430 cells; Colon; Homo sapiens (Human); CVCL_7040
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
• Mechanism Description: Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [11], [76], [85]

• Molecule Alteration: Missense mutation; p.D820E
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography assay; Direct sequencing assay
• Experiment for Drug Resistance: Computerized tomography/positron emission tomography imaging assay
• Mechanism Description: This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [11]

• Molecule Alteration: Missense mutation; p.D816G
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography assay; Direct sequencing assay
• Experiment for Drug Resistance: Computerized tomography/positron emission tomography imaging assay
• Mechanism Description: This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [11]

• Molecule Alteration: Missense mutation; p.D716N
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography assay; Direct sequencing assay
• Experiment for Drug Resistance: Computerized tomography/positron emission tomography imaging assay
• Mechanism Description: This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [11]

• Molecule Alteration: Missense mutation; p.D820Y
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Denaturing high-performance liquid chromatography assay; Direct sequencing assay
• Experiment for Drug Resistance: Computerized tomography/positron emission tomography imaging assay
• Mechanism Description: This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [12]

• Molecule Alteration: Dimerisation; Up-regulation
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5 GIST tissues; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: These results demonstrated that the c-kit mutation drove auto-dimerisation, and promoted receptor phosphorylation, and ligand-independent receptor signalling pathway. Therefore, dimerisation is the common step in both the activation processes of KIT prior to phosphorylation and therefore, blocking receptor dimerisation may be more effective than blocking the phosphorylated receptor.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: CCDC26 long non-coding RNA (CCDC26) [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Down-regulation of LncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation.

Key Molecule: CCDC26 long non-coding RNA (CCDC26) [15]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: CCDC26 knockdown enhanced imatinib resistance in GIST cells and c-kIT knockdown reversed the imatinib resistance mediated by CCDC26 inhibition.

Key Molecule: hsa-miR-125a-5p [87]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous kIT mutation but not in GIST48 cells with double kIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, kIT mutational status and survival.

Key Molecule: hsa-mir-320 [88]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320a was downregulated in imatinib-resistant GISTs and low expression of miR-320a was found to be associated with short TTR. This confirmed that miR-320a was involved in the process of imatinib resistance.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [89], [78]

• Molecule Alteration: Missense mutation; p.K642E
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: Secondary kIT mutations were identified in 11/14 (78.6%) imatinib-acquired-resistance patients, with nine patients in kIT gene exon17, and the other two in exon 13. The expressions of p-kIT, p-AkT, PCNA and BCL-2 were higher in the samples of imatinib-resistant GISTs than those of imatinib-responsive ones. P-kIT, p-AkT expressions were higher in imatinib acquired-resistance GISTs with secondary kIT mutations than imatinib-responsive ones with primary mutation. Total kIT, MAPk, p-MAPk, p-MTOR expressions were comparable in all varied GISTs.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Down-regulation of LncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [15]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: CCDC26 knockdown enhanced imatinib resistance in GIST cells and c-kIT knockdown reversed the imatinib resistance mediated by CCDC26 inhibition.

Key Molecule: Tyrosine-protein phosphatase non-receptor type 18 (PTPN18) [87]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GIST882 cells; Gastric; Homo sapiens (Human); CVCL_7044
• In Vitro Model: GIST48 cells; Gastric; Homo sapiens (Human); CVCL_7041
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous kIT mutation but not in GIST48 cells with double kIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, kIT mutational status and survival.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [90]

• Molecule Alteration: Missense mutation; p.V600E
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS/RAF/Mek/ERK signaling pathway; Activation; hsa04010
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: High-performance liquid chromatography screening assay
• Mechanism Description: This finding, in combination with the loss of kIT expression, suggests the possibility of activation of RAS-RAF-MEk-ERk pathways driven by a kIT-independent oncogenic mechanism. Most mutations lie within the kinase domain with a single nucleotide substitution at position 1799 in exon 15, leading to the V600E amino-acid substitution (98 %).

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [91]

• Molecule Alteration: Missense mutation; p.D842_D846>G
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/STAT3 signaling pathway; Activation; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Radiological response evaluation assay; Pathological response evaluation assay
• Mechanism Description: The most common PDGFRA mutation, a D842_D846delinsG shows primary resistance to imatinib in the patients.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [91]

• Molecule Alteration: Missense mutation; p.I843_S847>T
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/STAT3 signaling pathway; Activation; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Radiological response evaluation assay; Pathological response evaluation assay
• Mechanism Description: The most common PDGFRA mutation, a D842V substitution in exon 18, shows primary resistance to imatinib in in vitro and in vivo studies.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [9], [10], [11]

• Molecule Alteration: Missense mutation; p.D842V
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/STAT3 signaling pathway; Activation; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Radiological response evaluation assay; Pathological response evaluation assay
• Mechanism Description: The most common PDGFRA mutation, a I843_S847delinsT shows primary resistance to imatinib in the patients.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [92]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis Detection assay
• Mechanism Description: miRNA-21 sensitizes gastrointesti.l stromal tumors (GISTs) cells to Imatinib via targeting B-cell lymphoma 2 (Bcl-2), miRNA-21 suppressed Bcl-2 expression in GIST cells and could function as a potent tumor suppressor in GIST.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [92]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis Detection assay
• Mechanism Description: miRNA-21 sensitizes gastrointesti.l stromal tumors (GISTs) cells to Imatinib via targeting B-cell lymphoma 2 (Bcl-2), miRNA-21 suppressed Bcl-2 expression in GIST cells and could function as a potent tumor suppressor in GIST.

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) [5]

• 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.

Kidney cancer [ICD-11: 2C90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [12]

• Molecule Alteration: Dimerisation; Up-regulation
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: These results demonstrated that the c-kit mutation drove auto-dimerisation, and promoted receptor phosphorylation, and ligand-independent receptor signalling pathway. Therefore, dimerisation is the common step in both the activation processes of KIT prior to phosphorylation and therefore, blocking receptor dimerisation may be more effective than blocking the phosphorylated receptor.

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