Secondary mutations as mediators of resistance to targeted therapy in leukemia.

Abstract

The advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance.

• Authors: Naval Daver, Jorge Cortes, Farhad Ravandi, Keyur P Patel, Jan A Burger, Marina Konopleva, Hagop Kantarjian
• Journal: Blood (Blood) Vol. 125 Issue 21 Pg. 3236-45 (May 21 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25795921 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases

Topics

• Antineoplastic Agents (therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Leukemia (drug therapy, genetics)
• Mutation
• Protein Kinase Inhibitors (therapeutic use)
• Protein-Tyrosine Kinases (genetics)