Mechanisms of resistance to FGFR1 inhibitors in FGFR1-driven leukemias and lymphomas: implications for optimized treatment

Abstract

Myeloid and lymphoid neoplasms with eosinophilia and FGFR1 rearrangements (MLN-eo FGFR1) disease is derived from a pluripotent hematopoietic stem cell and has a complex presentation with a myeloproliferative disorder with or without eosinophilia and frequently presents with mixed lineage T-or B-lymphomas. The myeloproliferative disease frequently progresses to AML and lymphoid neoplasms can develop into acute lymphomas. No matter the cell type involved, or clinical presentation, chromosome translocations involving the FGFR1 kinase and various partner genes, which leads to constitutive activation of downstream oncogenic signaling cascades. These patients are not responsive to treatment regimens developed for other acute leukemias and survival is poor. Recent development of specific FGFR1 inhibitors has suggested an alternative therapeutic approach but resistance is likely to evolve over time. Mouse models of this disease syndrome have been developed and are being used for preclinical evaluation of FGFR1 inhibitors. Cell lines from these models have now been developed and have been used to investigate the mechanisms of resistance that might be expected in clinical cases. So far, a V561M mutation in the kinases domain and deletion of PTEN have been recognized as leading to resistance and both operate through the PI3K/AKT signaling axis. One of the important consequences is the suppression of PUMA, a potent enforcer of apoptosis, which operates through BCL2. Targeting BCL2 in the resistant cells leads to suppression of leukemia development in mouse models, which potentially provides an opportunity to treat patients that become resistant to FGFR1 inhibitors. In addition, elucidation of molecular mechanisms underlying FGFR1-driven leukemias and lymphomas also provides new targets for combined treatment as another option to bypass the FGFR1 inhibitor resistance and improve patient outcome.

A truncated derivative of FGFR1 kinase cooperates with FLT3 and KIT to transform hematopoietic stem cells in syndromic and de novo AML

“…Targeting FGFR1 activation with a variety of drugs has proved effective in suppressing leukemia cell growth in vitro and leukemogenesis in mouse models of SCLL [9,10], as well as in SCLL patients [11,12] and hence is potentially an effective way of treating this disease using targeted therapies. Resistance to these inhibitors, however, can develop [13,14], in part due to mutation in the kinase domain, which prevents binding of drugs targeting its phosphoactivation [15]. FGFR1, upon ligand activation, normally recruits intermediate signaling molecules [1] which activate cytoplasmic proteins to promote proliferation, suppress apoptosis and maintain the stem cell phenotype in SCLL.…”