March 28, 2025

Resistance mechanism in chronic lymphocytic leukemia identified

Resistance mechanism in chronic lymphocytic leukemia identified

Researchers at the German Cancer Research Center (DKFZ) have succeeded in identifying a resistance mechanism that often occurs in a specific targeted therapy against chronic lymphocytic leukemia (CLL). The drug ibrutinib is effective in many cases, but therapy resistance often develops during the course of treatment. In cell culture experiments and in mice, the resistance mechanism was successfully overcome using a second drug.

The drug ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor. These agents, which have only been available for about ten years, have significantly improved the treatment options for chronic lymphocytic leukemia: BTK inhibitors have a targeted effect on the malignant B cells in CLL. They slow down their uncontrolled proliferation by blocking the Bruton’s tyrosine kinase. This enzyme plays an important role in the maturation and proliferation of B cells.

Ibrutinib initially shows a good effect in many patients. However, the enormous adaptability of cancer cells enables them to become resistant to cancer drugs. As a result, the drug loses its therapeutic effect in almost all CLL patients over time, and the disease returns. The cancer cells become resistant and then grow even more aggressively than before. Alternative treatment options are urgently needed in this situation.

Are proteasome inhibitors the solution?

A research group led by Martina Seiffert from the German Cancer Research Center has been investigating the mechanisms that cause B cells to become resistant to ibrutinib. The team generated a mouse model of ibrutinib resistance in which the effect of the drug shows the same progression as in humans: Initially, it is highly effective, but as treatment continues, the disease returns and the malignant B cells proliferate rapidly. The researchers took leukemia cells from mice at various stages of this process and examined how genetic activity patterns and protein profiles in the cancer cells changed. This showed that changes occur in proteasome activity.

The proteasome is a cellular recycling system in which damaged proteins are broken down so that the building blocks can be reused. The altered activity of the proteasome during ibrutinib treatment suggests that the breakdown of proteins plays a role in the development of resistance. The use of proteasome inhibitors, which can be used to shut down proteasome activity, confirmed that this is the case.

In fact, the proteasome inhibitor carfilzomib led to longer survival in CLL mice with ibrutinib resistance. The researchers have apparently discovered a treatment option that is effective against ibrutinib-resistant CLL. The proteasome inhibitors also worked in cultured human B cells taken from CLL patients who were resistant to ibrutinib. These agents could therefore be an option in the future for the treatment of CLL patients who develop resistance to BTK inhibitors. The efficacy of this treatment option in CLL patients must now be tested in clinical trials.
 

Arseni, L et al: Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL. Nat Commun 2025: 16, 1041. https://doi.org/10.1038/s41467-025-56318-7

Our latest News

discover more
SPT Labtech and Agilent Introduce Automated Target Enrichment Protocols for Genomic Workflows

SPT Labtech and Agilent Introduce Automated Target Enrichment Protocols for Genomic Workflows

Cambridge, UK, 08 October 2025: SPT Labtech, a pioneer in the design and development of laboratory automation and liquid handling solutions, and Agilent Technologies Inc. (“Agilent”), a global leader in analytical and clinical laboratory technologies, today announced the introduction of automated target enrichment protocols on SPT Labtech’s firefly®+ platform. Automating genomic workflows, the optimized Target […]

PHOENIX fördert Forschung: Pharmazie Wissenschaftspreis für Pharmazeutische Technologie verliehen

PHOENIX fördert Forschung: Pharmazie Wissenschaftspreis für Pharmazeutische Technologie verliehen

Herzlichen Glückwunsch an JunProf. Dr. Philipp Uhl von der Universität Heidelberg und sein Team. Für PHOENIX ist das eine ganz besondere Auszeichnung, denn als approbierter Apotheker mit Schwerpunkt in der pharmazeutischen Forschung verbindet Philipp Uhl Praxis und Forschung – genau das, was die pharmazeutische Versorgung von morgen braucht. Die Forschung des Teams könnte die Arzneimitteltherapie verändern: […]

No more problems with reflective surfaces

No more problems with reflective surfaces

Start-up nanoAR receives funding from a federal “exist”-Forschungstransfer grant for its anti-reflective surface technology Most people have been irritated by the reflection of sunlight on their smartphone display or their spectacles. Many solutions are available — but until now none for curved surfaces or situations with a wide range of light incidence angles. Scientists at […]

GET IN TOUCH

Stay Updated with bioRN’s Newsletter

Sign up for our newsletter to discover more!
* required

BioRN (BioRN Network e.V. and BioRN Cluster Management GmbH) will use the information you provide on this form to be in touch with you and to provide updates and marketing. Please let us know all the ways you would like to hear from us:

You can update your subscription preferences or unsubscribe at any time. Just follow the unsubscribe or update link in the footer of automated emails you receive from us, or by contacting us at info@biorn.org. We will treat your information with respect. For more information about our privacy practices please visit our website: www.biorn.org. By clicking below, you agree that we may process your information in accordance with these terms.

We use Mailchimp as our marketing platform. By clicking below to subscribe, you acknowledge that your information will be transferred to Mailchimp for processing. Learn more about Mailchimp's privacy practices.

Intuit Mailchimp