Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia

Thomas O'Hare, Michael W.N. Deininger, Christopher A. Eide, Tim Clackson, Brian J. Druker

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABLT315I. A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABLT315I. The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABLT315I mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABL T315I in the development pipeline.

Original languageEnglish (US)
Pages (from-to)212-221
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number2
DOIs
StatePublished - Jan 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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