ArticleThe New England journal of medicine2022
Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.
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Article in The New England journal of medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 154 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
154citing papers in PubMed, 1 pooled it
32.3field-weighted citation impact, top 1% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
154 citing papers in PubMed, 1 synthesis or guideline pooled it, 225 citations in OpenAlex.
- Response to therapy in Richter syndrome: a systematic review with meta-analysis of early clinical trials.Frontiers in immunology · 2023Pooled it
- 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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- Long-term follow-up of MRD-guided ibrutinib plus venetoclax in relapsed CLL: phase 2 VISION/HO141 trial.Blood advances · 2025Trial
- Pirtobrutinib in Chinese patients with relapsed or refractory B-cell malignancies: A single-arm, open-label, phase 2, multicenter trial.International journal of cancer · 2025Trial
- Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study.Blood advances · 2025Trial
- Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study.Leukemia · 2024Trial
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- From prediction to performance:International journal of pharmaceutics: X · 2026Article
- Advances in molecular pathobiology of PCNSL - towards clinical implementation of novel diagnostics and therapeutics.Biomarker research · 2026Review
- Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases.MedComm · 2026Review
- Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.Molecular therapy. Oncology · 2026Review
- Sequencing asymmetry: the case for caution before first-line pirtobrutinib in chronic lymphocytic leukemia.Annals of hematology · 2026Article
- PLCG2 exon-skipped variants: insights into their potential role in chronic lymphocytic leukemia.Blood advances · 2026Article
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Atomic-level protein-ligand recognition with PBCNet2.0 for probe discovery.Nature chemical biology · 2026Article
- Australasian chronic lymphocytic leukaemia consensus statement: 2026 update.Internal medicine journal · 2026Article
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- Zanubrutinib and pirtobrutinib show synergistic killing and suppression of BTK signaling in MYD88-mutated lymphoma cells.Blood advances · 2026Article
- Single low-dose daratumumab enhances rituximab efficacy for sustained remission in treatment-refractory autoimmune cytopenias.Annals of hematology · 2026Article
94 more citing papers are in PubMed but not listed here.
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Authors and funding
35 authors at 1 institution in 1 country.
Eric WangFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Xiaoli MiFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Meghan C ThompsonFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Skye MontoyaFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Ryan Q NottiFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Jumana AfaghaniFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Benjamin H DurhamFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Alex PensonFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Matthew T WitkowskiFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Sydney X LuFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Jessie BourcierFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Simon J HoggFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Caroline EricksonFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Dan CuiFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Hana ChoFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Michael SingerFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Tulasigeri M TotigerFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Sana ChaudhryFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Mark GeyerFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Alvaro AlencarFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).ORCID 0000-0002-1720-9295
Adam J LinleyFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
M Lia PalombaFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Catherine C CoombsFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Jae H ParkFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Andrew ZelenetzFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Lindsey RoekerFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).ORCID 0000-0002-3806-059X
Mary RosendahlFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Donald E TsaiFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Kevin EbataFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Barbara BrandhuberFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
David M HymanFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Iannis AifantisFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Anthony MatoFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
Justin TaylorFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).ORCID 0000-0003-4407-6325
Omar Abdel-WahabFrom the Human Oncology and Pathogenesis Program (E.W., X.M., B.H.D., A.P., S.X.L., J.B., S.J.H., C.E., D.C., H.C., M.S., O.A.-W.), the Leukemia Service (M.C.T., M.G., J.H.P., L.R., A.M., O.A.-W.), and the Lymphoma Service (M.L.P., A.Z.), Department of Medicine, and the Department of Pathology (B.H.D.), Memorial Sloan Kettering Cancer Center, the Laboratory of Molecular Electron Microscopy, Rockefeller University (R.Q.N.), and the Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine (M.T.W., I.A.) - all in New York; Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami (S.M., J.A., T.M.T., S.C., A.A., J.T.); the Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom (A.J.L.); University of North Carolina Medical Center, Chapel Hill (C.C.C.); and Loxo Oncology at Lilly, Boulder, CO (M.R., D.E.T., K.E., B.B., D.M.H.).
MACOM (United States) · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MThe impact of changes in chromatin architecture on cancer phenotypes and tumor progressionP01CA229086 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI Effie Apostolou · 2019 to 2026
$17.0MThe Memorial Sloan Kettering Cancer Center SPORE in LeukemiaP50CA254838 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Eytan Stein · 2021 to 2026
$16.8MInvestigational Cancer Therapeutics Training Program (ICTTP)T32CA009207 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Omar Abdel-Wahab, Alexander Drilon · 1985 to 2026
$13.7MRole of TET2 mutations in malignant transformation and acute myeloid leukemiaR01CA173636 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI AIFANTIS, IANNIS, LEVINE, ROSS L · 2013 to 2022
$6.3MTargeting an RNA Binding Protein Network in Acute Myeloid LeukemiaR01CA242020 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI ABDEL-WAHAB, OMAR, AIFANTIS, IANNIS · 2020 to 2024
$2.7MRegulation of emergency hematopoiesis by the ubiquitin-proteasome systemR01HL159175 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI AIFANTIS, IANNIS, BUSINO, LUCA · 2021 to 2024
$2.5MThe cohesin complex as a tumor suppressor in myeloid leukemiaR01CA216421 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI AIFANTIS, IANNIS, LEVINE, ROSS L · 2017 to 2021
$2.5MMechanisms of enhancer regulation in leukemiaR01CA228135 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI AIFANTIS, IANNIS · 2019 to 2023
$2.5MDefining the Biological and Mechanistic Implications of XPO1 Mutations in Hematologic MalignanciesK08CA230319 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI TAYLOR, JUSTIN · 2018 to 2023
$1.2MInvestigating Resistance Mechanisms to Non-covalent Bruton's Tyrosine Kinase Inhibitors and Therapeutic Approaches to Overcome Resistance for Patients with B-Cell MalignanciesF31CA275378 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI MONTOYA, OLIVIA SKYE · 2022 to 2023
$94kNCI NIH HHS F31 CA275378NCI NIH HHS K08 CA230319NCI NIH HHS P01 CA229086NCI NIH HHS P30 CA008748NCI NIH HHS P50 CA254838NCI NIH HHS R01 CA173636NCI NIH HHS R01 CA216421NCI NIH HHS R01CA216421, R01CA173636, R01CA228135, P01CA229086NCI NIH HHS R01 CA228135NCI NIH HHS R01 CA242020NCI NIH HHS T32 CA009207NHLBI NIH HHS R01 HL159175
Abstract
backgroundCovalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood.
methodsWe performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors.
resultsAmong 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors.
conclusionsResistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.).
Indexed as
Agammaglobulinaemia Tyrosine KinaseDrug Resistance, NeoplasmLeukemia, Lymphocytic, Chronic, B-CellMutationPhospholipase C gammaProtein Kinase InhibitorsAdenineHumansMiddle AgedPiperidinesPyrazolesReceptors, Antigen, B-CellSequence Analysis, RNASignal TransductionAdenineAgammaglobulinaemia Tyrosine KinaseBTK protein, humanibrutinibPhospholipase C gammaPiperidinespirtobrutinibPLCG2 protein, humanProtein Kinase InhibitorsPyrazolesReceptors, Antigen, B-Cell
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