Compositions and methods for treating chemotherapy resistant cancer
The present invention features methods for increasing sensitivity and/or reversing resistance to chemotherapy, methods for treating or preventing a cancer in a subject, methods for treating clonal hematopoiesis of indeterminate potential in a subject, and methods of identifying resistance or sensitivity to chemotherapy in a subject. In some embodiments, the methods contain the step of administering an agent that inhibits the expression or activity of a Protein phosphatase 1D (PPM1D) polypeptide or polynucleotide. The present invention also features compositions for increasing sensitivity and/or reversing resistance to chemotherapy.
1. A method of increasing sensitivity or reversing resistance of a blood or hematologic cancer cell to a chemotherapeutic agent or inhibiting proliferation of a blood or hematologic cancer cell, the method comprising contacting the blood or hematologic cancer cell which is or has become resistant to a chemotherapeutic agent with an effective amount of a Protein phosphatase 1D (PPM1D) inhibitor, thereby increasing sensitivity or reversing resistance of the blood or hematologic cancer cell to the chemotherapeutic agent, or inhibiting proliferation.
2. The method of claim 1 , wherein the blood or hematologic cancer cell is in a subject having a blood or hematologic cancer.
3. The method of claim 2 , wherein the method treats the blood or hematologic cancer in the subject.
4. The method of claim 1 , wherein the blood or hematologic cancer cell is in vivo or in vitro.
5. The method of claim 1 , wherein the PPM1D inhibitor is selected from the group consisting of GSK2830371, CCT007093, and analogs thereof.
6. The method of claim 1 , wherein the chemotherapeutic agent is a DNA damaging agent selected from the group consisting of Cytarabine, Doxorubicin, Cyclophosphamide, and Cisplatin.
7. The method of claim 1 , wherein the PPM1D inhibitor inhibits the activity of a PPM1D polypeptide comprising a truncation mutation and/or a gain-of-function mutation.
8. The method of claim 2 , wherein the blood or hematologic cancer cell is a hematologic cancer cell.
9. The method of claim 2 , wherein the blood or hematologic cancer cell is a therapy-related myeloid neoplasm.
10. The method of claim 2 , wherein the blood or hematologic cancer cell is derived from blood, bone marrow or a tumor sample.