title: Strategies to circumvent the T315I gatekeeper mutation in the Bcr-Abl tyrosine kinase.
abstract: Despite the remarkable success of imatinib against Bcr-Abl, development of secondary resistance, most often due to point mutations in the Bcr-Abl tyrosine kinase (TK) domain, is quite common. Of these, the T315I "gatekeeper" mutation is resistant to all currently registered Bcr-Abl TK inhibitors (TKIs) with the notable exception of ponatinib (Iclusig™), which was very recently approved by the United States Food and Drug Administration (FDA). Besides ponatinib, numerous strategies have been developed to circumvent this problem. These include the protein synthesis inhibitor omacetaxine (Synribo®), and "switch-control" inhibitors. Dual Bcr-Abl and aurora kinase inhibitors represent another promising strategy. Finally, several promising synergistic combinations, such as TKIs with histone deacetylase inhibitors (HDACIs), warrant attention.
authors: Massey Cancer Center, Virginia Commonwealth University, Richmond, VA ; Departments of Internal Medicine, Virginia Commonwealth University, Richmond, VA.
authors: Prithviraj
authors: P
authors: Bose
authors: Haeseong
authors: H
authors: Park
authors: Jawad
authors: J
authors: Al-Khafaji
authors: Steven
authors: S
authors: Grant
keywords: AT9283; Bcr-Abl; Gatekeeper mutations; HDAC inhibitors; T315I; homoharringtonine; omacetaxine; ponatinib
references: Science. 2001 Aug 3;293(5531):876-80
references: 11423618
references: Cancer Cell. 2009 Nov 6;16(5):401-12
references: 19878872
references: Cancer Cell. 2011 Apr 12;19(4):556-68
references: 21481795
references: Blood. 2008 Aug 1;112(3):793-804
references: 18505786
references: Clin Cancer Res. 2011 May 15;17(10):3219-32
references: 21474579
references: Blood. 2012 Sep 27;120(13):2573-80
references: 22896000
references: Cancer. 2009 Dec 1;115(23):5382-93
references: 19739234
references: N Engl J Med. 2003 Oct 9;349(15):1451-64
references: 14534339
references: Blood. 2010 Sep 23;116(12):2089-95
references: 20548094