Mechanism of resistance to bet bromodomain inhibitors
AssigneeDana-Farber Cancer Institute, Inc.
InventorsKornelia Polyak, Shaokun Shu, James E. Bradner, Charles Yang Lin
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Abstract
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.
Claims20
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.
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.
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.
Dependencies are inferred from the claim text.