# Understanding mechanisms of BTK inhibitor and degrader resistance in patients with chronic lymphocytic leukemia

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $351,131

## Abstract

Project Summary
Covalent inhibitors of Bruton’s tyrosine kinase (BTK) are effective in multiple B-cell malignancies but patients
discontinue these agents due to resistance and intolerance. Highly selective and reversible non-covalent BTK
inhibitors have been developed to overcome these problems and are currently being tested in clinical trials in
patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Despite these beneficial
features of non-covalent BTK inhibitors and a high overall response rate seen in early clinical trials, some
patients did not respond to treatment or relapsed after initial response to monotherapy. This project’s broad
and long-term goals are to better understand these resistance mechanisms leading to relapse and design
better combination strategies or use of novel drugs to overcome this resistance. Our specific aims are to
elucidate the molecular mechanisms of resistance to this novel class of BTK inhibitors by interrogating the
signaling pathways in mutant BTK cells that are kinase deficient. We plan to comprehensively evaluate the
dependence of kinase dead BTK mutations on potential surrogate kinases activated by mutant BTK. We are
also testing the requirement for BTK for survival and signaling in cells with PLCG2 mutations. Lastly, we will
identify the genomic basis for BTK degrader resistance. Given the widespread use of BTK inhibitors across
CLL and B-cell malignancies, and the increasing incidence of patients with acquired resistance to non-covalent
BTK inhibitors, the results of this study will have major therapeutic importance for patients with a variety of B-
cell malignancies. Our findings will inform future application of disease monitoring on non-covalent BTK
inhibitors and about the development of resistance mechanisms with BTK degraders that are now being used
in clinical trials.

## Key facts

- **NIH application ID:** 10943869
- **Project number:** 1R01CA292653-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Justin Taylor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $351,131
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943869

## Citation

> US National Institutes of Health, RePORTER application 10943869, Understanding mechanisms of BTK inhibitor and degrader resistance in patients with chronic lymphocytic leukemia (1R01CA292653-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10943869. Licensed CC0.

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