Drug Information

Drug (ID: DG00192) and It's Reported Resistant Information

• Name: Ponatinib
• Synonyms: Iclusig (TN)
• Indication:
  In total 1 Indication(s)
  Mature B-cell lymphoma [ICD-11: 2A85]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  Chronic myeloid leukemia [ICD-11: 2A20]; [2]
• Target: Fms-like tyrosine kinase 3 (FLT-3); FLT3_HUMAN; [1]
• Target: Proto-oncogene c-Ret (RET); RET_HUMAN; [1]
• Target: Tyrosine-protein kinase ABL1 (ABL); ABL1_HUMAN; [1]
• Target: Tyrosine-protein kinase Kit (KIT); KIT_HUMAN; [1]
• Formula: C29H27F3N6O
• IsoSMILES: CC1=C(C=C(C=C1)C(=O)NC2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)C#CC4=CN=C5N4N=CC=C5
• InChI: 1S/C29H27F3N6O/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39)
• InChIKey: PHXJVRSECIGDHY-UHFFFAOYSA-N
• PubChem CID: 24826799
• ChEBI ID: CHEBI:78543
• TTD Drug ID: D0H0EQ
• VARIDT ID: DR00204
• DrugBank ID: DB08901

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.T315I
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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) [2]

• Molecule Alteration: Missense mutation; p.T212R
• 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) [2]

• Molecule Alteration: Missense mutation; p.Q252H
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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) [2]

• Molecule Alteration: Missense mutation; p.M244V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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) [2]

• 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: 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• Molecule Alteration: Missense mutation; p.H396R
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• Molecule Alteration: Missense mutation; p.G250E
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• Molecule Alteration: Missense mutation; p.F359V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• Molecule Alteration: Missense mutation; p.F359I
• 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• Molecule Alteration: Missense mutation; p.F359C
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• Molecule Alteration: Missense mutation; p.F317L
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• Molecule Alteration: Missense mutation; p.E453K
• 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• 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: 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-29a-3p [1]

• 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 [1]

• 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 [1]

• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myc proto-oncogene protein (MYC) [1]

• 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) [1]

• 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) [1]

• 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: Cellular tumor antigen p53 (TP53) [3]

• Molecule Alteration: Missense mutation; p.V216M
• Resistant Disease: Chronic myelogenous leukemia [ICD-11: 2A20.3]
• 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: Po.tinib led to a decrease of ABL T315I positive transcripts from 47% before po.tinib treatment to 16% at the time of po.tinib resistance in this patient, suggesting that both TP53 and ABL mutations were present in the same clone and that the newly acquired TP53 mutation might have caused po.tinib resistance in this patient.

Key Molecule: GTPase Nras (NRAS) [3], [4]

• 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.

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.T315I
• Resistant Disease: Relapsed acute lymphocytic leukemia [ICD-11: 2B33.5]
• 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: BCR-ABL1 e8a2 variant (BCR-ABL1) [2]

• Molecule Alteration: Missense mutation; p.D276G
• Resistant Disease: Relapsed acute lymphocytic leukemia [ICD-11: 2B33.5]
• 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.

References

• Ref 1: Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells. Oncotarget. 2017 Jul 25;8(30):49451-49469. doi: 10.18632/oncotarget.17706.
• Ref 2: Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. doi: 10.1056/NEJMoa1205127.
• Ref 3: Dissecting Genomic Aberrations in Myeloproliferative Neoplasms by Multiplex-PCR and Next Generation Sequencing. PLoS One. 2015 Apr 20;10(4):e0123476. doi: 10.1371/journal.pone.0123476. eCollection 2015.
• Ref 4: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013 Aug 8;122(6):872-84. doi: 10.1182/blood-2013-05-501569. Epub 2013 Jun 26.