Mechanism of resistance to bet bromodomain inhibitors
The present disclosure provides combination therapy comprising a BET inhibitor and a protein phosphatase 2A (PP2A) activator, a B-cell lymphoma-2 (Bcl-2) inhibitor, a B-cell lymphoma-extra large (Bcl-xl) inhibitor, a casein kinase 2 (CK2) inhibitor, and/or a mediator complex subunit 1 (MED1) for cancer. The combination therapy is expected to be synergistic in treating the cancer, compared to the monotherapy. Methods for identifying a subject having a cancer that is resistant to or at risk of developing resistance to bromodomain and extra terminal (BET) inhibitor therapy are also provided.
1. A method for treating a cancer, the method comprising:
administering to a subject in need thereof a bromodomain and extra terminal (BET) inhibitor and a protein phosphatase 2A (PP2A) activator in an amount effective to treat the cancer, wherein the cancer is resistant to treatment by the BET inhibitor alone.
2. The method of claim 1 , wherein the BET inhibitor and the PP2A activator are synergistic in treating the cancer, compared to the BET inhibitor alone or the PP2A activator alone.
3. The method of claim 1 , wherein the BET inhibitor is a bromodomain-containing protein 2 (BRD2) inhibitor, bromodomain-containing protein 3 (BRD3) inhibitor, or bromodomain-containing protein 4 (BRD4) inhibitor.
4. The method of claim 3 , wherein the BET inhibitor is a small molecule.
5. The method of claim 4 , wherein the BET inhibitor is JQ1 or a derivative thereof.
6. The method of claim 1 , wherein the PP2A activator is a small molecule.
7. The method of claim 6 , wherein the PP2A activator is a phenothiazine compound or FTY720.
8. The method of claim 7 , wherein the phenothiazine compound is selected from the group consisting of chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine and pharmaceutically acceptable salts and esters thereof.
9. The method of claim 1 , wherein the BET inhibitor and the PP2A activator are administered concurrently or sequentially.
10. The method of claim 5 , wherein the PP2A activator is a small molecule.
11. The method of claim 10 , wherein the PP2A activator is a phenothiazine compound or FTY720.
12. The method of claim 11 , wherein the phenothiazine compound is selected from the group consisting of chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine and pharmaceutically acceptable salts and esters thereof.
13. A method for treating a cancer, the method comprising:
administering to a subject in need thereof a bromodomain and extra terminal (BET) inhibitor and a protein phosphatase 2A (PP2A) activator in an amount effective to treat the cancer, wherein the subject is identified as being in need thereof if a ratio of phosphorylated bromodomain-containing protein 4 (pBRD4) to un-phosphorylated BRD4 (BRD4) in a tumor sample obtained from the subject is increased as compared to a control ratio of pBRD4 to BRD4.
14. The method of claim 13 , wherein the BET inhibitor is JQ1 or a derivative thereof.
15. The method of claim 13 , wherein the PP2A activator is a phenothiazine compound or FTY720.
16. The method of claim 14 , wherein the PP2A activator is a phenothiazine compound or FTY720.
17. A method for treating a cancer, the method comprising:
administering to a subject in need thereof a bromodomain and extra terminal (BET) inhibitor and a protein phosphatase 2A (PP2A) activator in an amount effective to treat the cancer, wherein the subject is identified as being in need thereof if the BRD4 intracellular location of bromodomain-containing protein 4 (BRD4) in a tumor sample obtained from the subject is the nucleus.
18. The method of claim 17 , wherein the BET inhibitor is JQ1 or a derivative thereof.
19. The method of claim 17 , wherein the PP2A activator is a phenothiazine compound or FTY720.
20. The method of claim 18 , wherein the PP2A activator is a phenothiazine compound or FTY720.