Methods of Predicting Resistance to JAK Inhibitor Therapy

• US 20140004516A1
• Filed: 06/12/2013
• Published: 01/02/2014
• Est. Priority Date: 06/12/2012
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Sattler, Martin, Deshpande, Anagha, Griffin, James D.
• Granted Patent: US 10,155,987 B2
• Time in Patent Office: Days
• US Class Current: 435/6.11
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G01N 33/574 for cancer

Abstract

This present invention provides methods of treating of assessing/monitoring the responsiveness of a cancer cell to JAK inhibitor therapy.

Claims

1. A method of assessing the effectiveness of a JAK inhibitor treatment regimen of a subject having a myeloproliferative malignacy with the JAK2V617F mutation comprising:

obtaining a sample from the subject, and detecting the presence or absence of one or more point mutations selected from the group consisting of Y931C, G935R, R938L, 1960V, and E985K in the kinase domain of the JAK2V617F polypeptide, wherein the presence of the mutation indicates the subject is resistant to JAK inhibitor treatment.

2. The method of claim 1, wherein the JAK inhibitor is an ATP-competitive inhibitor.

3. The method of claim 1, wherein the JAK inhibitor is ruxolitinib, CYT-387, TG101348, AZD1480, lestaurtinib, tofacitinib, pacritinib, baricitinib, BMS-911543, LY2784544, XL019, or NS018.

4. The method of claim 1, wherein the myeloproliferative malignancy is polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, acute myeloid leukemia or myelodysplastic syndrome.

6. The method of claim 1, wherein the JAK inhibitor is an ATP-competitive inhibitor.

7. The method of claim 1, wherein the JAK inhibitor is ruxolitinib, CYT-387, TG101348, AZD1480, lestaurtinib, tofacitinib, pacritinib, baricitinib, BMS-911543, LY2784544, XL019, or NS018.

8. The method of claim 1, wherein the myeloproliferative malignacy is polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, acute myeloid leukemia or myelodysplastic syndrome.

5. A method of selecting a treatment regimen for a subject having a myeloproliferative malignancy with the JAK2V617F mutation comprising:

obtaining a sample from the subject, and detecting the presence or absence of one or more point mutations selected from the group consisting of Y931C, G935R, R938L, 1960V, and E985K in the kinase domain of the JAK2V617F polypeptide, wherein the absence of the mutation indicates the subject should receive JAK inhibitor treatment or the presence of the mutation indicates the subject should not receive JAK inhibitor treatment.

9. A kit for the detection of mutant JAK2V617F nucleic acid or polypeptide in a biological sample, the kit comprising a reagent that detects a mutation selected from the group consisting of Y931C, G935R, R938L, 1960V, and E985K in the JAK2 kinase domain and one or more secondary reagents.