A potential therapeutic target for FLT3-ITD AML: PIM1 kinase

Amir T. Fathi, Omotayo Arowojolu, Ian Swinnen, Takashi Sato, Trivikram Rajkhowa, Donald Small, Fredrik Marmsater, John E. Robinson, Stefan David Gross, Matthew Martinson, Shelley Allen, Nicholas C. Kallan, Mark Levis

Research output: Contribution to journalArticlepeer-review

Abstract

Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) mutation have a poor prognosis, and FLT3 inhibitors are now under clinical investigation. PIM1, a serine/threonine kinase, is up-regulated in FLT3-ITD AML and may be involved in FLT3-mediated leukemogenesis. We employed a PIM1 inhibitor, AR00459339 (Array Biopharma Inc.), to investigate the effect of PIM1 inhibition in FLT3-mutant AML. Like FLT3 inhibitors, AR00459339 was preferentially cytotoxic to FLT3-ITD cells, as demonstrated in the MV4-11, Molm-14, and TF/ITD cell lines, as well as 12 FLT3-ITD primary samples. Unlike FLT3 inhibitors, AR00459339 did not suppress phosphorylation of FLT3, but did promote the de-phosphorylation of downstream FLT3 targets, STAT5, AKT, and BAD. Combining AR00459339 with a FLT3 inhibitor resulted in additive to mildly synergistic cytotoxic effects. AR00459339 was cytotoxic to FLT3-ITD samples from patients with secondary resistance to FLT3 inhibitors, suggesting a novel benefit to combining these agents. We conclude that PIM1 appears to be closely associated with FLT3 signaling, and that inhibition of PIM1 may hold therapeutic promise, either as monotherapy, or by overcoming resistance to FLT3 inhibitors.

Original languageEnglish (US)
Pages (from-to)224-231
Number of pages8
JournalLeukemia Research
Volume36
Issue number2
DOIs
StatePublished - Feb 1 2012

Keywords

  • Acute myeloid leukemia
  • FLT3
  • Internal tandem duplication
  • PIM1 kinase
  • Targeted therapy

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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