Dataset Information

BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib.

ABSTRACT: Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the "gatekeeper" residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.

SUBMITTER: Estupinan HY

PROVIDER: S-EPMC8102192 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib.

Estupiñán H Yesid HY Wang Qing Q Berglöf Anna A Schaafsma Gerard C P GCP Shi Yuye Y Zhou Litao L Mohammad Dara K DK Mohammad Dara K DK Yu Liang L Vihinen Mauno M Zain Rula R Smith C I Edvard CIE

Leukemia 20210201 5

Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the "gatekeeper" residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants wer ...[more]

PMID: 33526860

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Project description:The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases.

Dataset Information

BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib.

Publications

BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib.

Similar Datasets

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