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Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.
Wang, Eric; Mi, Xiaoli; Thompson, Meghan C; Montoya, Skye; Notti, Ryan Q; Afaghani, Jumana; Durham, Benjamin H; Penson, Alex; Witkowski, Matthew T; Lu, Sydney X; Bourcier, Jessie; Hogg, Simon J; Erickson, Caroline; Cui, Dan; Cho, Hana; Singer, Michael; Totiger, Tulasigeri M; Chaudhry, Sana; Geyer, Mark; Alencar, Alvaro; Linley, Adam J; Palomba, M Lia; Coombs, Catherine C; Park, Jae H; Zelenetz, Andrew; Roeker, Lindsey; Rosendahl, Mary; Tsai, Donald E; Ebata, Kevin; Brandhuber, Barbara; Hyman, David M; Aifantis, Iannis; Mato, Anthony; Taylor, Justin; Abdel-Wahab, Omar.
Affiliation
  • Wang E; From 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.
  • Mi X; From 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.
  • Thompson MC; From 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.
  • Montoya S; From 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.
  • Notti RQ; From 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.
  • Afaghani J; From 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.
  • Durham BH; From 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.
  • Penson A; From 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.
  • Witkowski MT; From 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.
  • Lu SX; From 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.
  • Bourcier J; From 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.
  • Hogg SJ; From 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.
  • Erickson C; From 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.
  • Cui D; From 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.
  • Cho H; From 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.
  • Singer M; From 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.
  • Totiger TM; From 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.
  • Chaudhry S; From 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.
  • Geyer M; From 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.
  • Alencar A; From 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.
  • Linley AJ; From 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.
  • Palomba ML; From 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.
  • Coombs CC; From 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.
  • Park JH; From 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.
  • Zelenetz A; From 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.
  • Roeker L; From 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.
  • Rosendahl M; From 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.
  • Tsai DE; From 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.
  • Ebata K; From 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.
  • Brandhuber B; From 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.
  • Hyman DM; From 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.
  • Aifantis I; From 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.
  • Mato A; From 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.
  • Taylor J; From 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.
  • Abdel-Wahab O; From 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.
N Engl J Med ; 386(8): 735-743, 2022 02 24.
Article in En | MEDLINE | ID: mdl-35196427
ABSTRACT

BACKGROUND:

Covalent (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.

METHODS:

We 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.

RESULTS:

Among 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.

CONCLUSIONS:

Resistance 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.).
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Lymphocytic, Chronic, B-Cell / Drug Resistance, Neoplasm / Protein Kinase Inhibitors / Phospholipase C gamma / Agammaglobulinaemia Tyrosine Kinase / Mutation Limits: Humans / Middle aged Language: En Journal: N Engl J Med Year: 2022 Type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Lymphocytic, Chronic, B-Cell / Drug Resistance, Neoplasm / Protein Kinase Inhibitors / Phospholipase C gamma / Agammaglobulinaemia Tyrosine Kinase / Mutation Limits: Humans / Middle aged Language: En Journal: N Engl J Med Year: 2022 Type: Article