Journal Article

The Dual PIM/FLT3 Inhibitor MEN1703 Combines Synergistically With Gilteritinib in FLT3‐ITD‐Mutant Acute Myeloid Leukaemia

Ghiaur, Gabriel, Bisignano, Diego, Belli, Francesco, Iannitto, Maria Luisa, Irrissuto, Clelia, Bigioni, Mario, Zicari, Sonia, Merlino, Giuseppe, Tunici, Patrizia, Bellarosa, Daniela, Paoli, Alessandro, Bressan, Alessandro, Cirigliano, Elena, Talucci, Simone, Binaschi, Monica, Brzózka, Krzysztof, Fiascarelli, Alessio

2024

Overview

MEN1703 is a first‐in‐class, oral, Type I dual PIM/FMS‐like tyrosine kinase 3 inhibitor (FLT3i) investigated in a Phase I/II DIAMOND‐01 trial in patients with acute myeloid leukaemia (AML). Gilteritinib is a highly potent and selective oral FLT3i approved for the treatment of relapsed/refractory AML with FLT3 mutations. Although gilteritinib showed strong single‐agent activity in FLT3‐mutated AML, the development of gilteritinib resistance limits response durability, indicating the importance of novel combination strategies to improve disease outcome. PIM kinases govern FLT3‐ITD signalling and increased PIM kinase expression is found in samples from AML patients relapsing on FLT3i. Here, we report that the simultaneous inhibition of PIM and FLT3, through the combination of MEN1703 and gilteritinib, can consistently improve the in vitro/in vivo antitumor activity over the single agents, demonstrating the benefit of this combination. Moreover, we demonstrate that resistance to gilteritinib can be circumvented by combining MEN1703 with gilteritinib. MEN1703 interferes with FLT3 upregulation, Mcl‐1 overexpression and PIM kinase signalling, which are all involved in FLT3i resistance. We also show that MEN1703 downregulates stromal cytokines that promote cytokine‐mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment‐mediated resistance to FLT3 inhibitors.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: acute myeloid leukaemia / Acute myeloid leukemia / Aniline Compounds - pharmacology / Aniline Compounds - therapeutic use / Animals / Antitumor activity / Blast cells / Bone marrow / Bridged-Ring Compounds / Capillary electrophoresis / Cell Line, Tumor / Cytokines / Disease resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Drug Synergism / fms-Like Tyrosine Kinase 3 - antagonists & inhibitors / fms-Like Tyrosine Kinase 3 - genetics / fms-Like Tyrosine Kinase 3 - metabolism / Genes / Genomics / gilteritinib / Humans / Humidity / Kinases / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Medical prognosis / Medical research / MEN1703 / Mice / Microenvironments / Mutation / Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors / Myeloid Cell Leukemia Sequence 1 Protein - genetics / Myeloid Cell Leukemia Sequence 1 Protein - metabolism / Original / PIM/FLT3 kinase inhibitor / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Proteins / Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors / Proto-Oncogene Proteins c-pim-1 - genetics / Proto-Oncogene Proteins c-pim-1 - metabolism / Pyrazines - pharmacology / Pyrazines - therapeutic use / Pyrimidines / Reagents / Software / targeted therapy / Xenograft Model Antitumor Assays