Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
AML, Biological, Diseases, Therapies, enzyme inhibitors, Biological Processes, Myeloid Malignancies, signal transduction
We have recently described in vivo anti-tumor activity in MAPK-activated solid tumor models following treatment with ASTX029, a highly potent ERK inhibitor developed using fragment-based drug design. ASTX029 has a distinctive ERK binding mode which confers dual mechanism inhibition of ERK, inhibiting both the catalytic activity of ERK and its phosphorylation by MEK. Here, we demonstrate that ASTX029 is also active in AML models and potently inhibits in vitro and in vivo MAPK signaling and growth in these models.
Using a panel of 15 AML cell lines, we investigated sensitivity to ASTX029 in vitro. We observed that 8 cell lines bearing mutations leading to increased MAPK pathway signaling were sensitive to treatment with ASTX029 with an average IC50 value of 47 nM, in contrast to an average IC50 value of 1800 nM for cell lines without activating mutations. The phosphorylation of RSK, a direct substrate of ERK, was suppressed for up to 24 h following treatment with ASTX029 in vitro. We have previously demonstrated good oral bioavailability for ASTX029 and once daily dosing resulted in significant tumor growth inhibition in AML cell line xenograft models. To confirm target engagement in vivo, we examined MAPK signaling in xenograft tissue and observed inhibition of the phosphorylation of RSK and of ERK itself, consistent with the dual mechanism of action proposed for ASTX029.
In summary, the ERK inhibitor, ASTX029, has potent activity against MAPK-activated tumor models, including AML models, and is now being tested in a Phase 1/2 clinical trial in advanced solid tumors (NCT03520075). These data highlight its therapeutic potential for the treatment of AML in patients with mutations leading to MAPK pathway activation and support further investigation in these patient populations.
Disclosures: Hindley: Astex Pharmaceuticals: Current Employment. Fazal: Astex Pharmaceuticals: Current Employment. Munck: Astex Pharmaceuticals: Current Employment. Martins: Astex Pharmaceuticals: Current Employment. Shah: Astex Pharmaceuticals: Current Employment. Wilsher: Astex Pharmaceuticals: Current Employment. Wallis: Astex Pharmaceuticals: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Lyons: Astex Pharmaceuticals: Current Employment.
See more of: Oral and Poster Abstracts