The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile

Christopher A. Eide, Lauren T. Adrian, Jeffrey W. Tyner, Mary Mac Partlin, David J. Anderson, Scott C. Wise, Bryan D. Smith, Peter A. Petillo, Daniel L. Flynn, Michael W.N. Deininger, Thomas O'Hare, Brian J. Druker

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Acquired point mutations within the BCR-ABL kinase domain represent a common mechanismof resistance to ABL inhibitor therapy in patients with chronic myeloid leukemia (CML). The BCR-ABLT315I mutant is highly resistant to imatinib, nilotinib, and dasatinib, and is frequently detected in relapsed patients. This critical gap in resistance coverage drove development of DCC-2036, an ABL inhibitor that binds the switch control pocket involved in conformational regulation of the kinase domain. We evaluated the efficacy of DCC-2036 against BCRABLT315I and other mutants in cellular and biochemical assays and conducted cell-based mutagenesis screens. DCC-2036 inhibited autophosphorylation of ABL and ABLT315I enzymes, and this activity was consistent with selective efficacy against Ba/F3 cells expressing BCR-ABL (IC50: 19 nmol/L), BCR-ABLT315I (IC50: 63 nmol/L), and most kinase domain mutants. Ex vivo exposure ofCML cells from patients harboring BCR-ABL or BCR-ABLT315I to DCC-2036 revealed marked inhibition of colony formation and reduced phosphorylation of the direct BCR-ABL target CrkL. Cell-based mutagenesis screens identified a resistance profile for DCC-2036 centered around select Ploop mutations (G250E, Q252H, Y253H, E255K/V), although a concentration of 750 nmol/L DCC-2036 suppressed the emergence of all resistant clones. A decreased concentration of DCC-2036 (160 nmol/L) in dual combination with either nilotinib or dasatinib achieved the same zero outgrowth result. Further screens for resistance due to BCR-ABL compound mutations (two mutations in the same clone) identified BCR-ABLE255V / T315I as the most resistant mutant. Taken together, these findings support continued evaluation of DCC-2036 as an important new agent for treatment-refractory CML.

Original languageEnglish (US)
Pages (from-to)3189-3195
Number of pages7
JournalCancer Research
Volume71
Issue number9
DOIs
StatePublished - May 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABL<sup>T315I</sup> and exhibits a narrow resistance profile'. Together they form a unique fingerprint.

  • Cite this

    Eide, C. A., Adrian, L. T., Tyner, J. W., Partlin, M. M., Anderson, D. J., Wise, S. C., Smith, B. D., Petillo, P. A., Flynn, D. L., Deininger, M. W. N., O'Hare, T., & Druker, B. J. (2011). The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile. Cancer Research, 71(9), 3189-3195. https://doi.org/10.1158/0008-5472.CAN-10-3224