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. ⋯ 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.).
Eric Wang, Xiaoli Mi, Meghan C Thompson, Skye Montoya, Ryan Q Notti, Jumana Afaghani, Benjamin H Durham, Alex Penson, Matthew T Witkowski, Sydney X Lu, Jessie Bourcier, Simon J Hogg, Caroline Erickson, Dan... more Cui, Hana Cho, Michael Singer, Tulasigeri M Totiger, Sana Chaudhry, Mark Geyer, Alvaro Alencar, Adam J Linley, M Lia Palomba, Catherine C Coombs, Jae H Park, Andrew Zelenetz, Lindsey Roeker, Mary Rosendahl, Donald E Tsai, Kevin Ebata, Barbara Brandhuber, David M Hyman, Iannis Aifantis, Anthony Mato, Justin Taylor, and Omar Abdel-Wahab. less
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... more 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.). less
N. Engl. J. Med. 2022 Feb 24; 386 (8): 735743735-743.