Publication in Science: Treatment-induced resistance mutations in BTK can be overcome by a clinical-stage BTK degrader

Sigrid S. Skånland, project group leader at Department of Cancer Immunology, did a research stay at Memorial Sloan Kettering Cancer Center in New York in 2022. The work she did while she was in the group of Dr. Omar Abdel-Wahab has now been published in Science.

Bruton’s tyrosine kinase (BTK) inhibitors are used to treat the B-cell malignancy chronic lymphocytic leukemia (CLL). Resistance mutations to the first generation of inhibitors are well characterized and have formed the rationale for a new generation of inhibitors. However, also these lead to alterations in BTK over time.

In the Science article, BTK inhibitor resistance mutations were characterized in detail, and it was shown that kinase impaired BTK still has an oncogenic scaffold function. To overcome this function, BTK degraders have been developed.

“I was first introduced to BTK degraders during a research stay in Dr. Adrian Wiestner’s lab at NIH in 2019”, Skånland says. “However, at that time, they were not clinically mature. The publication in Science includes results from a phase I trial with the BTK degrader NX-2127 in CLL”.

The results provide the first evidence that BTK degradation is achievable in humans and that they may be associated with clinical responses even in patients with previously described and newly discovered resistance mutations.

Skånland’s stay in New York was supported by Norsk Hydros Fond for Kreftforskning and Radiumhospitalets Legater. Aleksandra Urban, former PostDoc in Skånland’s group, is a co-author on the publication.

Sigrid S. Skånland
Omar Abdel-Wahab
Aleksandra Urban

Links:

The Science publication:
Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127 | Science

Sigrid Skånland’s project group

Department of Cancer Immunology

Institute for Cancer Research

The Omar-Abdel Wahab lab at Memorial Sloan Kettering Cancer Center in New York:
The Omar Abdel-Wahab Lab | Sloan Kettering Institute (mskcc.org)

Pre-clinical study from NIH on BTK degrader
NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts | Blood | American Society of Hematology (ashpublications.org)

 

 
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