An Overview of Bruton Tyrosine Kinase Inhibition


Harry P. Erba, MD, PhD:Welcome to thisTargeted Oncologypresentation titled “BTK Inhibition in B-Cell Lymphomas.” I am Dr Harry Erba, professor of medicine and director of the leukemia program at Duke University in Durham, North Carolina.

Our discussion today will focus on an important therapeutic class that has revolutionized the treatment of several hematologic cancers. Beginning with the approval of ibrutinib in 2013, these novel BTK [Bruton tyrosine kinase] inhibitors represent a paradigm-changing advance in precision oncology.

Please join me in welcoming my colleague, Dr Anthony Mato, a hematologic oncologist and director of the CLL [chronic lymphocytic leukemia] program at the Memorial Sloan Kettering Cancer Center, in New York, New York. Welcome, Dr Mato.

Anthony R. Mato, MD, MSCE:Hi, thanks for having me.

Harry P. Erba, MD, PhD:Well, let’s get started. The name, Bruton, I remember from medical school, Bruton agammaglobulinemia. Clearly this must have something to do with Bruton tyrosine kinase. Can you explain what BTKs are?

Anthony R. Mato, MD, MSCE:Sure. BTK is an enzyme that’s part of the B-cell receptor signaling pathway. You’re right. Originally, the X-linked agammaglobulinemia was described by Colonel Ogden Bruton, who was in the military. This is one of the early downstream signal amplification enzymes of the B-cell receptor that helps to amplify the signal between the receptor and the nucleus.

Harry P. Erba, MD, PhD:And the B-cell receptor is immunoglobulin?

Anthony R. Mato, MD, MSCE:Immunoglobulin, essentially the contact point between the B-cell receptor and antigen, either foreign or host.

Harry P. Erba, MD, PhD:What would be the rationale then for using inhibitors of BTK in lymphomas?

Anthony R. Mato, MD, MSCE:B-cell lymphomas, in general, are heavily dependent on B-cell receptor signaling. You can get into the individual lymphomas and discuss whether it’s independent or antigen driven. But essentially, their survival, their migration, their proliferation are very heavily dependent on that particular signaling, even more so than their analogous B-cell lymphocytes. And so, the hypothesis there would be that blocking that signal would inhibit one of the key survival signals in these lymphomas, and hopefully that would trigger cell death.

Harry P. Erba, MD, PhD:Is there a difference in the involvement in BTK in, for example, a lymphocyte that’s pre-germinal center, that has not yet seen antigen, and post-germinal center, the mutated immunoglobulin gene rearrangement, for example, in CLL?

Anthony R. Mato, MD, MSCE:Absolutely. The different lymphomas, whether or not they’ve been through the germinal center, really have an effect on whether the B-cell receptor has been antigen exposed. And so, you could argue in a lymphoma like follicular lymphoma, B-cell receptor signaling may be secondary to chronic antigen stimulation. Whereas in other lymphomas like a DLBCL [diffuse large B-cell lymphoma], for example, there may not be chronic signaling but active signaling at the receptor, itself.

Harry P. Erba, MD, PhD:So we’ve been talking about B cells. Are there other cells that depend on BTK and signaling?

Anthony R. Mato, MD, MSCE:Not BTK specifically, but BTK as part of a family called the TEC kinases. And there are analogous kinases involved in lymphocyte signaling—for example, ITK in a lymphocyte. But there are TEC kinases that are involved in signal amplification in many cells of the body.

Harry P. Erba, MD, PhD:It’s interesting to know that BTK is part of a family, and it makes me wonder, with the inhibitors that we’re about to discuss, is there activity of those inhibitors against other kinases in that family, besides BTK?

Anthony R. Mato, MD, MSCE:A good example is ibrutinib, which is a first-in-class BTK inhibitor approved for treating patients with B-cell malignancies. BTK is certainly inhibited by ibrutinib, but there are several other related kinases that can be inhibited as well. So there is certainly other activity in other cells, which may lend to the development of these drugs in other malignancies, like solid tumors, possibly, but also may be heavily dependent on the AE [adverse event] profile of the drugs. Many of the adverse events we see could be, potentially, off-target effects.

Transcript edited for clarity.

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