Targeting Met And Fgfr In Relapsed Or Refractory Acute Myeloid Leukemia: Preclinical, Clinical, And Correlative Studies

Background: Increased expression of hepatocyte growth factor (HGF), causing activation of its receptor MET, is found in a subset of patients with acute myeloid leukemia (AML). Inhibition of HGF-MET signaling with the specific MET kinase inhibitor crizotinib led to a transient therapeutic effect in AML cells; however, resistance rapidly emerged via increased HGF expression due to activation of alternative kinase pathways such as FGFR1 (Kentsis et al., Nat Medicine, 2012). Thus, simultaneous inhibition of activated MET and FGFR represents a potential therapeutic opportunity to forestall resistance to MET inhibition, in part by promoting downregulation of oncogenic STAT transcription factors. The MET/RON inhibitor merestinib and the pan-FGFR inhibitor LY2874455 are investigational small molecules. While they have been tested as single agents in phase 1 solid tumor cancer trials, they have neither been tested individually or in combination in AML patients (pts).