ArticleBlood advances2023
Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance.
Article in Blood advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 78 citations in OpenAlex.
- Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations.Blood cancer journal · 2026Trial
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- Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study.Blood advances · 2025Trial
- Preclinical and clinical efficacy of the HDAC6 inhibitor ricolinostat in combination with BCR pathway inhibitors in relapsed/refractory chronic lymphocytic leukemia.Blood cancer journal · 2026Article
- Computational hybrid framework integrating clinical-mutation profiling and physics-based simulations to predict structural tolerance of Bruton tyrosine kinase (BTK) and sustained ARQ 531 binding.Current research in structural biology · 2026Article
- Have Fixed-Duration (FD) Regimens Delivered on Their Promise in Chronic Lymphocytic Leukemia and What Is the Future of FD Regimens? A Narrative Review.Advances in therapy · 2026Review
- When Targeted Therapy Falls Short: Unraveling Resistance Mechanisms in Chronic Lymphocytic Leukemia.Current hematologic malignancy reports · 2026Review
- Mechanisms of resistance to bruton's tyrosine kinase inhibitors: synergistic effects of tumor microenvironment regulation and signaling pathways.Annals of hematology · 2026Review
- Targeting Bruton's Tyrosine Kinase (BTK) in Autoimmunity: Achievements, Opportunities and Challenges.Drug design, development and therapy · 2026Review
- Cardiovascular Safety of Bruton Tyrosine Kinase Inhibitors: From Ibrutinib to Next-Generation Agents.American journal of cardiovascular drugs : drugs, devices, and other interventions · 2026Review
- Generational safety profiles of BTK inhibitors: adverse reaction signals and real-world evidence from the FAERS database.Frontiers in medicine · 2026Article
- Drug resistance in cancer: molecular mechanisms and emerging treatment strategies.Molecular biomedicine · 2025Review
- Genes-first and phenotypes-first paths to treatment resistance in hematological malignancies.Cell death & disease · 2025Review
- Pirtobrutinib in the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma.Future oncology (London, England) · 2025Review
- Pharmacological profiling in CLL patients during pirtobrutinib therapy and disease progression.Blood cancer journal · 2025Article
- Pirtobrutinib in Chronic Lymphocytic Leukemia: Navigating Resistance and the Personalisation of BTK-Targeted Therapy.Cancers · 2025Review
- Next-generation Bruton tyrosine kinase inhibitors and degraders in the treatment of B-cell malignancies: advances and challenges.Annals of hematology · 2025Review
- Review
- Resistance mechanisms and approach to chronic lymphocytic leukemia after BTK inhibitor therapy.Leukemia & lymphoma · 2025Review
- Characteristics and outcomes of patients with double refractory and double exposed chronic lymphocytic leukemia.Blood advances · 2025Article
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Authors and funding
25 authors at 5 institutions in 2 countries.
Funding
Abstract
Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor (BCR) signaling, cell viability, and CCL3/CCL4 chemokine production in both BTK wild-type and C481S mutant CLL cells. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, cell survival, and CCL3/CCL4 chemokine secretion. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability, and cytokine production. We employed longitudinal whole-exome sequencing on 2 patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to noncovalent BTKis.
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