Coming of Age for BTK Inhibitor Therapy: A Review of Zanubrutinib in Waldenström Macroglobulinemia

Muñoz, Javier; Paludo, Jonas; Sarosiek, Shayna; Castillo, Jorge J.

doi:10.3390/cells11203287

Cited by 6 publications

(3 citation statements)

References 84 publications

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“…BTK inhibitors have changed the treatment land-scape of the B cell malignancies chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (1,(4)(5)(6)(7). Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind BTK at cysteine 481 (C481) and prevent BTK autophosphorylation at tyrosine 223 (Y223) as well as phosphorylation of BTK's downstream substrates (4,(8)(9)(10).…”

Section: Rationalementioning

confidence: 99%

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

Montoya,

Bourcier,

Noviski

et al. 2024

Science

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Increasing use of covalent and noncovalent inhibitors of Bruton’s tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

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Section: Rationalementioning

confidence: 99%

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

Montoya,

Bourcier,

Noviski

et al. 2024

Science

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“…The BTK inhibitor zanubrutinib has been approved for the treatment of mantle cell lymphoma and Waldenström's macroglobulinemia [21]. Regarding its use in haemato-oncological malignancies, zanubrutinib has similar or slightly improved selectivity towards kinases in the TEC and ERBB families compared to ibrutinib, yet it is less potent than acalabrutinib [10].…”

Section: Introductionmentioning

confidence: 99%

Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines

Dostalova

Jorda

Řezníčková

et al. 2023

Preprint

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Small molecule Bruton's tyrosine kinase inhibitors have been developed for the treatment of various haemato-oncological diseases, and ibrutinib was approved as the first BTK inhibitors for anticancer therapy in 2013. Previous reports proved the receptor kinase human epidermal growth factor receptor 2 (HER2) to be a valid off-target kinase of ibrutinib and potentially other irreversible BTK inhibitors, as it possesses a druggable cysteine residue in the active site of the enzyme. These findings suggest ibrutinib as a candidate drug for repositioning in HER2-positive breast cancer. This subtype of breast cancer belongs to one of the most common classes of breast tumours, and its prognosis is characterized by a high rate of recurrence and tumour invasiveness. Based on their similar kinase selectivity profiles, we investigated the anticancer effect of zanubrutinib, evobrutinib, tirabrutinib and acalabrutinib in different BCa cell lines and sought to determine whether it is linked with targeting the epidermal growth factor receptor family (ERBB) pathway. We found that zanubrutinib is a potential inhibitor of the HER2 signalling pathway, displaying an antiproliferative effect in HER2-positive breast cancer cell lines. Zanubrutinib effectively inhibits the phosphorylation of proteins in the ERBB signalling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells. We thus propose zanubrutinib as another suitable candidate for repurposing in HER2-amplified solid tumours.

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“…The BTK inhibitor zanubrutinib has been approved for the treatment of mantle cell lymphoma and Waldenström's macroglobulinemia [21]. Regarding its use in haematooncological malignancies, zanubrutinib has similar or slightly improved selectivity towards kinases in the TEC and ERBB families compared to ibrutinib, yet it is less potent than acalabrutinib [10].…”

Section: Introductionmentioning

confidence: 99%

Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines

et al. 2023

View full text Add to dashboard Cite

Small molecule Bruton’s tyrosine kinase (BTK) inhibitors have been developed for the treatment of various haemato-oncological diseases, and ibrutinib was approved as the first BTK inhibitor for anticancer therapy in 2013. Previous reports proved the receptor kinase human epidermal growth factor receptor 2 (HER2) to be a valid off-target kinase of ibrutinib and potentially other irreversible BTK inhibitors, as it possesses a druggable cysteine residue in the active site of the enzyme. These findings suggest ibrutinib as a candidate drug for repositioning in HER2-positive breast cancer (BCa). This subtype of breast cancer belongs to one of the most common classes of breast tumours, and its prognosis is characterized by a high rate of recurrence and tumour invasiveness. Based on their similar kinase selectivity profiles, we investigated the anticancer effect of zanubrutinib, evobrutinib, tirabrutinib and acalabrutinib in different BCa cell lines and sought to determine whether it is linked with targeting the epidermal growth factor receptor family (ERBB) pathway. We found that zanubrutinib is a potential inhibitor of the HER2 signalling pathway, displaying an antiproliferative effect in HER2-positive BCa cell lines. Zanubrutinib effectively inhibits the phosphorylation of proteins in the ERBB signalling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells. We thus propose zanubrutinib as another suitable candidate for repurposing in HER2-amplified solid tumours.

show abstract

Coming of Age for BTK Inhibitor Therapy: A Review of Zanubrutinib in Waldenström Macroglobulinemia

Cited by 6 publications

References 84 publications

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines

Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines

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