Secondary mutations as mediators of resistance to targeted therapy in leukemia

Naval Daver, Jorge Cortes, Farhad Ravandi, Keyur P. Patel, Jan A. Burger, Marina Konopleva, Hagop Kantarjian

Research output: Contribution to journalArticle

55 Scopus citations

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. Secondgeneration 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 inhibitorresistant 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 thirdgeneration inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance.

Original languageEnglish (US)
Pages (from-to)3236-3245
Number of pages10
JournalBlood
Volume125
Issue number21
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Daver, N., Cortes, J., Ravandi, F., Patel, K. P., Burger, J. A., Konopleva, M., & Kantarjian, H. (2015). Secondary mutations as mediators of resistance to targeted therapy in leukemia. Blood, 125(21), 3236-3245. https://doi.org/10.1182/blood-2014-10-605808