The rise and fall of gatekeeper mutations? The BCR‐ABL1 T315I paradigm

• Published in: Cancer Vol. 118; no. 2; pp. 293 - 299
• Main Authors: Gibbons, Don L., Pricl, Sabrina, Kantarjian, Hagop, Cortes, Jorge, Quintás‐Cardama, Alfonso
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.01.2012
• Subjects: Antineoplastic Agents - pharmacology; Benzamides; chronic myeloid leukemia; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl - chemistry; Fusion Proteins, bcr-abl - genetics; gatekeeper mutation; Humans; Imatinib Mesylate; Imidazoles - pharmacology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Mutation; Piperazines; ponatinib; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Pyridazines - pharmacology; Pyrimidines; threonine‐to‐isoleucine mutation at codon 315; tyrosine kinase inhibitor
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.26225

The use of tyrosine kinase inhibitors (TKIs) has become an integral component of cancer therapy. Imatinib mesylate, a breakpoint cluster region‐Abelson BCR‐ABL1 inhibitor, was the first TKI approved in cancer medicine and has served as a model for the development of similar agents for other cancers. An important drawback of TKI therapy is the development of resistance, frequently through the acquisition of mutations. Mutations at the gatekeeper residues of BCR‐ABL1 (eg, the threonine‐to‐isoleucine mutation at codon 315) and other oncogenic kinases have proven highly resistant to currently available TKIs. Advances in the structural biology of oncogenic kinases have facilitated the rational development of TKIs that are active against gatekeeper mutations. Cancer 2011;. © 2011 American Cancer Society. Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic myeloid leukemia (CML). However, the development of resistance breakpoint cluster region/Abelson murine leukemia 1 (BCR‐ABL1) mutations impair their activity. The gatekeeper threonine‐to‐isoleucine mutation at codon 315 (T315I) produces complete insensitivity to all currently approved TKIs in CML. Other mutated gatekeeper residues in a variety of oncogenic kinases that drive the pathogenesis of different human cancers have proven highly resistant to TKI therapy. Advances in the structural biology of oncogenic kinases have facilitated the rational development of TKIs that are active against gatekeeper mutations, which are exemplified best by ponatinib in CML.