Homo sapiens Targeted Locus (Loci)

Development of effective targeted cancer therapeutics depends upon distinguishing disease-associated “driver” mutations, which play causative roles in malignancy pathogenesis, from “passenger” mutations dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate “driver” from “passenger” lesions and provide insights into disease biology. Activating in-tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukemia (AML) patients and are associated with poor prognosis. Abundant scientific and clinical, evidence, including inability of early FLT3 inhibitors to achieve significant clinical remissions, suggests that FLT3-ITD mutations likely represent “passenger” lesions. Here we identify point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an investigational inhibitor of FLT3, KIT, PDGFR and RET6 and the first inhibitor to demonstrate convincing clinical activity in FLT3-ITD+ AML. We detected evolution of AC220-resistant substitutions at two of these amino acid positions in eight of eight FLT3-ITD AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD is a “driver” lesion in a proportion of AML patients and highlight clinically relevant AC220-resistant FLT3 kinase domain mutants that represent high-value targets for future FLT3 inhibitor development.