Bruton tyrosine kinase (BTK) is a critical component in the signaling cascade of the B-cell receptor (BCR). The BCR pathway is utilized by normal B-cells as well as by malignant B-cells. This pathway comprises multiple kinases and several adaptor proteins. The activation of the BCR leads to the intracellular signaling events that result in the growth, survival, and migration of B-cells. In several B-cell malignancies, the BCR signaling pathway is aberrantly activated by the malignant cells. As a result, the inhibition of BTK can interfere with the signaling required for the survival of the malignant B-cells.

These differences are also important for clinicians to understand when deciding between various targeted therapies and to understand the effects of BTK inhibition on their patients.

B-Cell Receptor Signaling and BTK

BCR signaling leads to B-cell proliferation, migration, and survival through the action of multiple kinases and adaptor proteins. In the BCR signaling complex, BTK is an essential component that becomes phosphorylated on Tyr697 upon BCR activation. Activated BTK then can phosphorylate and activate other signaling molecules in the B-cell, including PLCγ2, Vav, and PKC. These in turn can regulate a variety of cellular processes, including B-cell proliferation, migration, survival, and tumor cell interaction with the tumor microenvironment. In several B-cell malignancies, these signaling pathways become dysregulated or are exploited by malignant cells. Inhibiting BTK can therefore interfere with signals that support malignant B-cell survival.

In several types of B-cell malignancies, the B-cell receptor signaling pathway is dysregulated and even exploited by the malignant cells. Therefore, inhibition of BTK in the malignant B-cells by BTK inhibitors interferes with survival signals that are required for growth and survival of the malignant B cells.

The B-cell receptor (BCR) signaling pathway is utilized by many B-cell malignancies for growth and survival. By inhibiting BTK, the BCR signaling pathway may be disrupted, leading to the death of the malignant B-cells. The first generation of BTK inhibitors were covalent BTK inhibitors. They covalently attached to BTK creating a covalent bond between the BTK inhibitor and BTK for extended periods of time. This class of drugs has led to the development of many newer BTK inhibitors.

These first generation BTK inhibitors form covalent adducts with BTK leading to sustained inhibition of BTK. In the years that followed, a new class of BTK inhibitors has been developed described as second generation. These new compounds have been designed to have greater selectivity for BTK with less activity against other kinases, often referred to as off-target kinases, in order to minimize the adverse effects of these other inhibited kinases.

Covalent BTK Inhibition

Off-target kinase inhibition can cause undesirable side effects. Therefore, BTK inhibitors with high selectivity for BTK are of clinical interest. Different BTK inhibitors, even those with similar IC50 values for BTK, will have different off-target activities for other kinases. This will result in differences in side effects and tolerability.

There are several second generation covalent BTK inhibitors in the market, such as Acalabrutinib (Calquence) and Zanubrutinib (Brukinsa). BTK inhibitors drugs have distinct molecular structures, and consequently, distinct prescribing information.

Understanding Differences Between BTK Inhibitors

Different BTK inhibitor drugs targeting the same BTK molecule should not be considered as interchangeable agents because each of the agents has different selectivity profiles, dosing frequencies, pharmacokinetic properties, drug interactions, and clinical trial data.

The clinical trials and resulting data that are used to assess the safety and efficacy of the different BTK inhibitors vary in terms of the patient population under study. Thus, for example, the data for one drug may have been generated in a clinical trial of patients with a certain type of B cell malignancy, whereas the data for another drug may have been generated in a clinical trial of patients with a different type of B cell malignancy.

Just because a number of compounds can inhibit BTK does not mean that all of these compounds can be used in the same way. The extent to which any given compound can inhibit BTK in any given clinical setting is a function of a number of pharmacokinetic properties and of a number of drug interactions. In the end, the key to any of these compounds is the clinical evidence that supports their use.

B-Cell Signaling and Treatment Response

The initial dependence of a malignant cell on B cell signaling for its survival and proliferation is not the only factor which determines the treatment response of a patient with a B cell malignancy. In CLL with TP53 aberrations (e.g. TP53 mutations and deletions of 17p), patients are classified as being of high risk of disease progression and alternative treatment options need to be considered on an individual basis.

The malignant cells themselves can also receive signals that promote their growth and survival from the surrounding stromal cells and the host’s immune cells. In fact, treatment with BTK inhibitors can result in the redistribution of malignant lymphocytes from the lymphoid tissues (where they receive growth promoting signals) to the peripheral blood (where they may receive less growth promoting signals and die).

Mechanisms of Resistance

However, resistant cancer cells have been found to harbor acquired mutations in the BTK kinase or in downstream signaling molecules, rendering BTK inhibitors less effective in treating leukemia or lymphoma.

Several resistance mutations have been identified that affect activity of covalent BTK inhibitors. In an effort to overcome resistance to covalent BTK inhibitors, several non-covalent or reversible BTK inhibitors are in early to mid-stage clinical development. It is critical that when a patient’s disease is progressing on a BTK inhibitor, the clinician understands the molecular mechanism(s) of resistance to that particular drug, as different BTK inhibitors (covalent and non-covalent) have different activities against different BTK alterations that confer resistance to covalent BTK inhibitors.

Translating Molecular Biology Into Clinical Decisions

Molecular targeting of cancer does not imply that clinicians are able to stop thinking about their patients. In reality, molecular targeted therapy can be used in a wide range of tumors. Thus, clinicians have to make decisions on a case-by-case basis. For the treatment of B-cell malignancies with BTK inhibitors, there are a number of factors that need to be taken into account.

However, the targeted therapy for cancer does not mean that clinical decisions can be left to the molecular targeting. There are many factors that still need to be considered, for example, the type of cancer, the previous treatment, the molecular characteristics of the cancer, the co-morbidities of the patients, the other medications that the patients are taking, the potential side effects of the treatment and the preferences of the patients.

Clinical evidence from specific studies on the use of individual BTK inhibitors in distinct patient populations is required to support their use. Studies on treatment-naïve patients with CLL, for example, will not automatically translate to heavily pretreated patients with CLL of similar disease. Furthermore, studies on individual B-cell malignancies will not automatically translate to other B-cell malignancies.

Implications for Combination Strategies

For the most part of this review we focus on the use of single BTK inhibitors in different B cell malignancies; however, in some situations BTK inhibition may be most effective in combination with BCL2 inhibition and/or with anti-CD20 mAbs (either humanized or human versions).

In summary, by targeting different aspects of B-cell survival, combination treatment with BTK-inhibition can lead to deeper responses and potentially allow for modification of treatment duration in specific cases.

On the other hand, combination of targeted therapies may add many complexities to the treatment, including new toxicities and drug interactions. Thus, clinical evidence will be required to assess benefits of combination for individual patient populations.

The Future of BTK-Directed Therapy

Future directions for BTK inhibition include next generation covalent inhibitors as well as non-covalent (reversible) BTK inhibitors, and combinations of BTK inhibitors with other agents that target critical pathways for the survival of malignant B cells.

BTK inhibition is a way to attack the signaling networks that sustain the malignant B cells. In order to make optimal treatment choices for patients with B cell malignancies, an understanding of the B cell signaling networks and their dysregulation in cancer is required.

Clinical Perspective

Targeted therapy using increasing selectivity for BTK, and a better understanding of the rest of the kinase family, translates knowledge of the B-cell receptor signaling pathway into treatment of B-cell malignancies using drugs such as Calquence and Brukinsa.

Healthcare professionals need to continue to understand the basic biology of the disease, the molecular pathology of individual cancers, the mechanisms of resistance to individual drugs, and the clinical evidence that supports the use of BTK inhibitors in individual clinical circumstances.

Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.

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