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A change in the enzyme BTK at the exact point where the drug grips it. The enzyme keeps working and the drug no longer holds, which is the usual reason a BTK inhibitor stops working after it has been working well.
Ibrutinib and its covalent successors bind cysteine 481 of BTK irreversibly. Whole-exome sequencing of paired baseline and relapse samples from six patients with acquired resistance found a cysteine-to-serine substitution at that residue in five of them, and three distinct PLCG2 mutations in two; functional work showed that C481S leaves the protein only reversibly inhibited, and that the PLCG2 changes R665W and L845F are gain-of-function lesions producing autonomous B-cell receptor activity. Neither was found in nine patients with prolonged lymphocytosis who were still responding (Woyach 2014).
The answer to C481S is a non-covalent inhibitor that does not need the cysteine. Pirtobrutinib produced an overall response of 73.3% in 247 patients who had already received a covalent BTK inhibitor, with median progression-free survival of 19.6 months (Mato 2023). Resistance to that in turn runs through different residues: the kinase-dead L528W substitution was found in 7 of 13 patients progressing on zanubrutinib against 1 of 24 on ibrutinib, and in two patients it was enriched further under pirtobrutinib, which is cross-resistance rather than a new event; both of those patients responded to venetoclax afterwards (Blombery 2022).
In plain words · The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.
If a BTK inhibitor has stopped working, this test can say whether a different BTK inhibitor is still worth trying or whether the next treatment needs to work in another way altogether, such as venetoclax, a bispecific antibody or CAR-T. A report that says only BTK mutated has not answered the question; the exact change matters.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
Deep targeted sequencing of BTK and PLCG2 on blood or marrow at progression, reported by specific residue rather than as BTK mutated, because the residue decides what works next: C481 substitutions are answered by a non-covalent inhibitor, while L528W and T474I are not. Subclonal variants at low allele fraction can appear months before clinical progression, so the depth of the assay matters.
“We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients.”
Woyach et al., New England Journal of Medicine 2014No approval uses this readout as a threshold. It is defined by Woyach et al., N Engl J Med 2014: BTK C481S and PLCG2 resistance mutations under ibrutinib.
Shares PLCG2, Pirtobrutinib, B-cell receptor / BTK signalling (to NF-κB), Zanubrutinib.
Shares B-cell receptor / BTK signalling (to NF-κB), BTK (Bruton tyrosine kinase), Ibrutinib, Next-generation sequencing (NGS) and the tags biomarker, lymphoma.
Shares Cross-resistance, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Comprehensive genomic profiling and the tags biomarker, resistance.
Shares Cross-resistance, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Comprehensive genomic profiling and the tags biomarker, resistance.
Shares Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Comprehensive genomic profiling, Liquid biopsy (ctDNA) and the tags biomarker, resistance.
Shares BCL2 G101V and the other venetoclax binding-site mutations, Venetoclax, Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.
Shares Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Comprehensive genomic profiling, Liquid biopsy (ctDNA) and the tags biomarker, resistance.
Shares Marginal zone lymphoma, Next-generation sequencing (NGS), Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.