Details

Autor(en) / Beteiligte

• Woyach, Jennifer A
• Furman, Richard R
• Liu, Ta-Ming
• Ozer, Hatice Gulcin
• Zapatka, Marc
• Ruppert, Amy S
• Xue, Ling
• Li, Daniel Hsieh-Hsin
• Steggerda, Susanne M
• Versele, Matthias
• Dave, Sandeep S
• Zhang, Jenny
• Yilmaz, Ayse Selen
• Jaglowski, Samantha M
• Blum, Kristie A
• Lozanski, Arletta
• Lozanski, Gerard
• James, Danelle F
• Barrientos, Jacqueline C
• Lichter, Peter
• Stilgenbauer, Stephan
• Buggy, Joseph J
• Chang, Betty Y
• Johnson, Amy J
• Byrd, John C

Titel

Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib

Ist Teil von

• The New England journal of medicine, 2014-06, Vol.370 (24), p.2286-2294

Ort / Verlag

Waltham, MA: Massachusetts Medical Society

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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, 1 pathway dysregulation in CLL results in the propagation of proliferative and prosurvival signals. 2 , 3 Several agents targeting the B-cell–receptor pathway are in development, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. Although BTK is not recurrently mutated in CLL, 4 , 5 it is up-regulated at the transcript level and is constitutively active. 6 , 7 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 . . .