The New England journal of medicine, 2014-06-12, Vol.370 (24), p.2286-2294
In some patients with CLL, resistance to the BTK inhibitor ibrutinib develops. Two classes of resistance mutations have been found: the more common involves alteration of the drug-binding site to make binding reversible; the less common activates a downstream kinase that effectively bypasses BTK.
The development of B-cell–receptor antagonists has been a therapeutic advance in chronic lymphocytic leukemia (CLL). Although B-cell–receptor ligation in normal cells induces proliferation, apoptosis, or anergy,
pathway dysregulation in CLL results in the propagation of proliferative and prosurvival signals.
Several agents targeting the B-cell–receptor pathway are in development, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. Although
is not recurrently mutated in CLL,
it is up-regulated at the transcript level and is constitutively active.
Ibrutinib irreversibly binds BTK at the C481 residue, rendering it kinase-inactive, inducing modest CLL-cell apoptosis, and abolishing proliferation and B-cell–receptor signaling in . . .
Biological and medical sciences ; General aspects ; Medical sciences ; Recurrence ; Phospholipase C gamma - metabolism ; Pyrazoles - therapeutic use ; Humans ; Middle Aged ; Binding Sites - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Pyrimidines - pharmacology ; Receptors, Antigen, B-Cell - metabolism ; Sequence Analysis, DNA ; Exome ; Point Mutation ; Drug Resistance, Neoplasm - genetics ; Protein-Tyrosine Kinases - genetics ; Pyrimidines - therapeutic use ; Agammaglobulinaemia Tyrosine Kinase ; Phospholipase C gamma - genetics ; Aged ; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Pyrazoles - pharmacology ; Tyrosine ; Cysteine ; Chronic lymphatic leukemia ; Serine ; Leukemia ; Genomes ; Lymphatic leukemia ; Kinases ; Bruton's tyrosine kinase ; Lymphocytes B ; Mutation ; Lymphocytosis ; Protein-tyrosine kinase ; Deoxyribonucleic acid--DNA ; Apoptosis ; Index Medicus ; Abridged Index Medicus
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