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Updated: Apr 15, 2026

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach

Atsushi Nonami1, Martin Sattler1, Ellen Weisberg1

  • 1Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA;

Blood
|April 3, 2015
PubMed

Insights

Researchers identified GNF-7, a compound that selectively kills cancer cells with NRAS mutations. This discovery offers a new strategy for targeting RAS oncogenes in hematologic malignancies and other cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Oncogenic NRAS mutations are prevalent in hematologic malignancies and other cancers, presenting significant therapeutic challenges.
  • Targeting individual NRAS downstream effectors often leads to resistance via bypass pathways.

Purpose of the Study:

  • To identify novel therapeutic targets in NRAS-transformed cancer cells.
  • To discover compounds with selective cytotoxicity against NRAS-dependent cells.

Main Methods:

  • A chemical screen was conducted using mutant NRAS-transformed Ba/F3 cells.
  • Compound GNF-7 was identified and its mechanism of action was analyzed.
  • Preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia were used.

Main Results:

  • GNF-7 demonstrated potent and selective inhibition of NRAS-dependent cells.
  • The compound's effects were partly mediated by inhibiting ACK1/AKT and germinal center kinase (GCK).

Conclusions:

  • Small molecule screens can effectively identify novel therapeutic targets in RAS-driven cancers.
  • Combined inhibition of ACK1/AKT and GCK may be a viable strategy for NRAS-mutant cancers.

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