Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors
In this paper just published in PNAS, Dr. Lou Staudt and his colleagues at the United States National Cancer Institute and scientists from Constellation Pharmaceuticals demonstrated that combination of the recently approved drug, ibrutinib, with small molecule BET bromodomain inhibitors results in significantly enhanced killing of an aggressive subtype of non-Hodgkin lymphoma.
The activated B-cell like (ABC) subtype of diffuse large cell B-cell lymphoma (DLBCL) is an aggressive hematological malignancy. Although it can be effectively treated with a regimen that includes cytotoxic chemotherapy and the monoclonal antibody rituximab, only about 40% of patients with this subtype of DBCL are cured. ABC DLBCL tumors rely on constitutive activation of NF-kB-dependent gene transcription for their survival. Activation of NF-kB occurs through a cascade of signaling events, which provide a number of different points for pharmacologic intervention. Ibrutinib inhibits Bruton’s tyrosine kinase (BTK), which is activated by the B-cell receptor and lies upstream in the cascade. The paper published by Staudt and colleagues demonstrates that BET inhibitors inhibit the activity of IκB kinase (IKK), an enzyme that lies downstream in the cascade and is responsible for the release of NF-kB from its inactive cytosolic location. By simultaneously inhibiting these two targets the combination of ibrutinib and a BET inhibitor resulted in enhanced lymphoma cell killing in vitro and in increased suppression of lymphoma xenograft growth in vivo. Importantly, the greater control of lymphoma xenograft growth achieved with the combination occurred at well tolerated doses.
Ibrutinib (IMBRUVICA, Pharmacyclics Inc.), has been recently approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma and small lymphocytic lymphoma. It has also demonstrated activity in the treatment of patients with DLBCL. Constellation’s BET inhibitor, CPI-0610, is currently in a Phase I clinical trial in patients with a wide range of lymphomas, including DLBCL.
The results of this collaboration between Dr. Staudt and Constellation provide a rationale for the clinical evaluation of the combination of ibrutinib and small molecule BET bromodomain inhibitors in patients with ABC DLBCL.