Resistance To Flt3 Inhibitors

Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase 3 (FLT3) are the most common mutations in acute myeloid leukemia (AML) and lead to activated signaling through multiple pro-survival pathways. Clinically, FLT3-ITD mutations confer an increased risk of relapse and diminished overall survival. Clinical responses to monotherapy with first generation type I small molecule FLT3 inhibitors (midostaurin, lestaurtinib) were lackluster due to the lack of potency and pharmacokinetic profiles inadequate for sustained FLT3 inhibition. Treatment response rates have improved with more potent and selective second generation FLT3 inhibitors such as quizartinib, but pre-clinically predicted on-target secondary kinase domain (KD) mutations have arisen as the most common mechanism of clinical resistance, commonly at the gatekeeper F691 and D835 activation loop residues in the FLT3 KD. The highly selective, next generation type I FLT3 inhibitor crenolanib appears less vulnerable to KD mutations in vitro, but whole exome and ultra-deep sequencing of patients with progressive disease on crenolanib have found multiple "off-target" mutations in other genes including SF3B1, ASXL1, STAG2, and mediators in the RAS pathway. Off target mutation of the cell cycle regulator CCND3 leading to cyclin D3 overexpression and cell proliferation was also identified in patients with lack of response to the second-generation type II inhibitor PLX3397. Relapse remains a major problem for patients treated with FLT3 inhibitors. Further detailed characterization of both on and off-target resistance mechanisms will be needed to provide rationale for combination therapy that may improve clinical response rates and decrease risk of relapse.