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Ref Type Journal Article
PMID (33526860)
Authors Estupiñán HY, Wang Q, Berglöf A, Schaafsma GCP, Shi Y, Zhou L, Mohammad DK, Yu L, Vihinen M, Zain R, Smith CIE
Title BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib.
Journal Vol Issue Date Pages Journal Short Title
Leukemia 35 5 2021 05 1317-1329 Leukemia
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BTK T474A missense loss of function BTK T474A lies within the protein kinase domain of the Btk protein (UniProt.org). T474A confers a loss of function to Btk as demonstrated by reduced kinase activity in cell culture (PMID: 33526860, PMID: 21138328).
BTK T474E missense no effect - predicted BTK T474E lies within the protein kinase domain of the Btk protein (UniProt.org). T474E results in kinase activity similar to wild-type Btk as demonstrated by autophosphorylation levels of Y223 similar to wild-type protein in cell culture (PMID: 33526860), and therefore, is predicted to have no effect on Btk protein function.
BTK T474F missense no effect - predicted BTK T474F lies within the protein kinase domain of the Btk protein (UniProt.org). T474F results in kinase activity similar to wild-type Btk as demonstrated by autophosphorylation levels of Y223 similar to wild-type protein in cell culture (PMID: 33526860), and therefore, is predicted to have no effect on Btk protein function.
BTK T474I missense no effect BTK T474I lies within the protein kinase domain of the Btk protein (UniProt.org). T474I demonstrates kinase activity similar to wild-type Btk in cultured cells (PMID: 27571029, PMID: 28573668, PMID: 33526860).
BTK T474L missense gain of function - predicted BTK T474L lies within the protein kinase domain of the Btk protein (UniProt.org). T474L results in increased kinase activity as demonstrated by increased autophosphorylation of Y223 in cell culture (PMID: 33526860), and therefore, is predicted to lead to a gain of Btk protein function.
BTK T474N missense loss of function - predicted BTK T474N lies within the protein kinase domain of the Btk protein (UniProt.org). T474N results in reduced kinase activity as demonstrated by decreased autophosphorylation of Y223 in cell culture (PMID: 33526860), and therefore, is predicted to lead to loss of Btk protein function.
BTK T474P missense loss of function - predicted BTK T474P lies within the protein kinase domain of the Btk protein (UniProt.org). T474P results in reduced kinase activity as demonstrated by decreased autophosphorylation of Y223 in cell culture (PMID: 33526860), and therefore, is predicted to lead to loss of Btk protein function.
BTK T474Q missense no effect - predicted BTK T474Q lies within the protein kinase domain of the Btk protein (UniProt.org). T474Q results in kinase activity similar to wild-type Btk as demonstrated by autophosphorylation levels of Y223 similar to wild-type protein in cell culture (PMID: 33526860), and therefore, is predicted to have no effect on Btk protein function.
BTK T474S missense no effect - predicted BTK T474S lies within the protein kinase domain of the Btk protein (UniProt.org). T474S results in kinase activity similar to wild-type Btk as demonstrated by autophosphorylation levels of Y223 similar to wild-type protein in cell culture (PMID: 33526860), and therefore, is predicted to have no effect on Btk protein function.
BTK T474V missense no effect - predicted BTK T474V lies within the protein kinase domain of the Btk protein (UniProt.org). T474V results in kinase activity similar to wild-type Btk as demonstrated by autophosphorylation levels of Y223 similar to wild-type protein in cell culture (PMID: 33526860), and therefore, is predicted to have no effect on Btk protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK T474I Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in cell lines expressing BTK T474I in culture (PMID: 33526860). 33526860
BTK C481S Advanced Solid Tumor predicted - sensitive RN486 Preclinical - Biochemical Actionable In a preclinical study, treatment with RN486 resulted in reduced Btk activity in a cell line expressing BTK C481S in culture (PMID: 33526860). 33526860
BTK T474A BTK C481S Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in cell lines expressing BTK variants T474A and C481S in culture (PMID: 33526860). 33526860
BTK T474S Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in cell lines expressing BTK T474S in culture (PMID: 33526860). 33526860
BTK T474I BTK C481S Advanced Solid Tumor predicted - resistant CGI1746 Preclinical - Biochemical Actionable In a preclinical study, treatment with CGI1746 failed to inhibit Btk activity in a cell line expressing BTK variants T474I and C481S in culture (PMID: 33526860). 33526860
BTK T474M BTK C481S Advanced Solid Tumor predicted - resistant Acalabrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Calquence (acalabrutinib) failed to inhibit Btk activity in a cell line expressing BTK variants T474M and C481S in culture (PMID: 33526860). 33526860
BTK T474M BTK C481T Advanced Solid Tumor predicted - resistant Acalabrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Calquence (acalabrutinib) failed to inhibit Btk activity in a cell line expressing BTK variants T474M and C481T in culture (PMID: 33526860). 33526860
BTK T474M BTK C481S Advanced Solid Tumor predicted - sensitive RN486 Preclinical - Biochemical Actionable In a preclinical study, treatment with RN486 resulted in reduced Btk activity in a cell line expressing BTK variants T474M and C481S in culture (PMID: 33526860). 33526860
BTK C481T Advanced Solid Tumor predicted - sensitive RN486 Preclinical - Biochemical Actionable In a preclinical study, treatment with RN486 resulted in reduced Btk activity in a cell line expressing BTK C481T in culture (PMID: 33526860). 33526860
BTK T474I BTK C481S Advanced Solid Tumor predicted - resistant Zanubrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Brukinsa (zanubrutinib) failed to inhibit Btk activity in a cell line expressing BTK variants T474I and C481S in culture (PMID: 33526860). 33526860
BTK T474M BTK C481S Advanced Solid Tumor predicted - resistant CGI1746 Preclinical - Biochemical Actionable In a preclinical study, treatment with CGI1746 failed to inhibit Btk activity in a cell line expressing BTK variants T474M and C481S in culture (PMID: 33526860). 33526860
BTK C481S Advanced Solid Tumor predicted - sensitive Fenebrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Fenebrutinib resulted in reduced Btk activity in a cell line expressing BTK C481S in culture (PMID: 33526860). 33526860
BTK T474M BTK C481T Advanced Solid Tumor predicted - resistant CGI1746 Preclinical - Biochemical Actionable In a preclinical study, treatment with CGI1746 failed to inhibit Btk activity in a cell line expressing BTK variants T474M and C481T in culture (PMID: 33526860). 33526860
BTK T474M BTK C481T Advanced Solid Tumor predicted - sensitive RN486 Preclinical - Biochemical Actionable In a preclinical study, treatment with RN486 resulted in reduced Btk activity in a cell line expressing BTK variants T474M and C481T in culture (PMID: 33526860). 33526860
BTK T474A Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in cell lines expressing BTK T474A in culture (PMID: 33526860). 33526860
BTK T474Q Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in a cell line expressing BTK T474Q in culture (PMID: 33526860). 33526860
BTK T474M BTK C481T Advanced Solid Tumor predicted - resistant Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) failed to inhibit Btk activity in a cell line expressing BTK variants T474M and C481T in culture (PMID: 33526860). 33526860
BTK T474M BTK C481S Advanced Solid Tumor predicted - resistant Zanubrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Brukinsa (zanubrutinib) failed to inhibit Btk activity in a cell line expressing BTK variants T474M and C481S in culture (PMID: 33526860). 33526860
BTK T474M BTK C481T Advanced Solid Tumor predicted - sensitive Fenebrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Fenebrutinib (GDC-0853) resulted in reduced Btk activity in a cell line expressing BTK variants T474M and C481T in culture (PMID: 33526860). 33526860
BTK T474L Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in cell lines expressing BTK T474L in culture (PMID: 33526860). 33526860
BTK T474I BTK C481S Advanced Solid Tumor predicted - resistant Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) failed to inhibit Btk activity in a cell line expressing BTK variants T474I and C481S in culture (PMID: 33526860). 33526860
BTK T474M Advanced Solid Tumor predicted - resistant Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) failed to inhibit Btk activity in cell lines expressing BTK T474M in culture (PMID: 33526860). 33526860
BTK T474M Advanced Solid Tumor predicted - resistant Acalabrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Calquence (acalabrutinib) failed to inhibit Btk activity in a cell line expressing BTK T474M in culture (PMID: 33526860). 33526860
BTK T474M BTK C481S Advanced Solid Tumor predicted - sensitive Fenebrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Fenebrutinib (GDC-0853) resulted in reduced Btk activity in a cell line expressing BTK variants T474M and C481S in culture (PMID: 33526860). 33526860
BTK T474A BTK C481S Advanced Solid Tumor predicted - resistant Fenebrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Fenebrutinib (GDC-0853) failed to inhibit Btk activity in a cell line expressing BTK variants T474A and C481S in culture (PMID: 33526860). 33526860
BTK T474M BTK C481S Advanced Solid Tumor predicted - resistant Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) failied to inhibit Btk activity in a cell line expressing BTK variants T474M and C481S in culture (PMID: 33526860). 33526860
BTK T474V Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in cell lines expressing BTK T474V in culture (PMID: 33526860). 33526860
BTK T474S BTK C481S Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in a cell line expressing BTK variants T474S and C481S in culture (PMID: 33526860). 33526860
BTK T474S BTK C481S Advanced Solid Tumor predicted - sensitive Fenebrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Fenebrutinib (GDC-0853) resulted in reduced Btk activity in a cell line expressing BTK variants T474S and C481S in culture (PMID: 33526860). 33526860
BTK T474A Advanced Solid Tumor predicted - sensitive Fenebrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Fenebrutinib (GDC-0853) resulted in reduced Btk activity in a cell line expressing BTK T474A in culture (PMID: 33526860). 33526860
BTK T474E Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in cell lines expressing BTK T474E in culture (PMID: 33526860). 33526860
BTK T474I BTK C481S Advanced Solid Tumor predicted - sensitive RN486 Preclinical - Biochemical Actionable In a preclinical study, treatment with RN486 resulted in reduced Btk activity in a cell line expressing BTK variants T474I and C481S in culture (PMID: 33526860). 33526860
BTK T474I BTK C481S Advanced Solid Tumor predicted - resistant Acalabrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Calquence (acalabrutinib) failed to inhibit Btk activity in a cell line expressing BTK variants T474I and C481S in culture (PMID: 33526860). 33526860
BTK T474I BTK C481S Advanced Solid Tumor predicted - sensitive Fenebrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Fenebrutinib (GDC-0853) resulted in reduced Btk activity in a cell line expressing BTK variants T474I and C481S in culture (PMID: 33526860). 33526860
BTK T474N Advanced Solid Tumor predicted - sensitive Ibrutinib Preclinical - Biochemical Actionable In a preclinical study, treatment with Imbruvica (ibrutinib) resulted in reduced Btk activity in cell lines expressing BTK T474N in culture (PMID: 33526860). 33526860