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Abstract
Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 鈥榙river鈥?mutations, which have causative roles in malignancy pathogenesis, from 鈥榩assenger鈥?mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis1. Abundant scientific2 and clinical evidence1,3, including the lack of convincing clinical activity of early FLT3 inhibitors4,5, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET6,7; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts.
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Data deposits
SMRT sequencing data is deposited online at http:// www.ncbi.nlm.nih.gov/sra under accession number SRA050226.1.
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AcknowledgementsWe thank K. Lin for technical assistance. This work was funded by grants from the Leukemia and Lymphoma Society (to C.C.S. and N.P.S.), the Doris Duke Charitable Foundation (to N.P.S.), NCI Leukemia SPORE P50 CA100632-06 (to M.J.L.), NCI R01 CA12886 (to M.J.L.) and the NIH T-32 Molecular Mechanisms of Cancer (to C.C.S.). C.C.S. would like to acknowledge the EHA/ASH Translational Research Training Institute. N.P.S. would like to thank Art and Alison Kern and the Edward S. Ageno family for their support.
Author informationAuthor notesJeremy P. Hunt,聽Patrick P. Zarrinkar,聽Eric E. Schadt聽 聽Andrew KasarskisPresent address: Present addresses: KINOMEscan Division of DiscoveRx Corporation, San Diego, California 92121, USA (J.P.H.); Blueprint Medicines Corporation, Cambridge, Massachusetts 02142, USA (P.P.Z.); Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York 10029, USA (E.E.S. and A.K.).,
AffiliationsDivision of Hematology/Oncology, University of California, San Francisco, 94143, California, USACatherine C. Smith,聽Sara Salerno,聽Lauren E. Damon聽 聽Neil P. ShahDepartment of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USAQi Wang聽 聽John KuriyanPacific Biosciences, Menlo Park, 94025, California, USAChen-Shan Chin,聽Kevin J. Travers,聽Susana Wang,聽Eric E. Schadt聽 聽Andrew KasarskisDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, 21231, Maryland, USAMark J. LevisAbramson Cancer Center of the University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USAAlexander E. PerlAmbit Biosciences, San Diego, 92121, California, USAJeremy P. Hunt聽 聽Patrick P. ZarrinkarHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 94115, California, USANeil P. ShahAuthorsCatherine C. SmithView author publicationsYou can also search for this author in PubMed Google Scholar Qi WangView author publicationsYou can also search for this author in PubMed Google Scholar Chen-Shan ChinView author publicationsYou can also search for this author in PubMed Google Scholar Sara SalernoView author publicationsYou can also search for this author in PubMed Google Scholar Lauren E. DamonView author publicationsYou can also search for this author in PubMed Google Scholar Mark J. LevisView author publicationsYou can also search for this author in PubMed Google Scholar Alexander E. PerlView author publicationsYou can also search for this author in PubMed Google Scholar Kevin J. TraversView author publicationsYou can also search for this author in PubMed Google Scholar Susana WangView author publicationsYou can also search for this author in PubMed Google Scholar Jeremy P. HuntView author publicationsYou can also search for this author in PubMed Google Scholar Patrick P. ZarrinkarView author publicationsYou can also search for this author in PubMed Google Scholar Eric E. SchadtView author publicationsYou can also search for this author in PubMed Google Scholar Andrew KasarskisView author publicationsYou can also search for this author in PubMed Google Scholar John KuriyanView author publicationsYou can also search for this author in PubMed Google Scholar Neil P. ShahView author publicationsYou can also search for this author in PubMed Google Scholar ContributionsC.C.S., Q.W., C.-S.C., K.J.T., A.K., E.E.S. and J.K. designed experiments, performed research, analysed data and wrote the manuscript. N.P.S. designed experiments, analysed data and wrote the manuscript. L.E.D., S.W., J.P.H. and S.S. performed experiments and reviewed the manuscript. P.P.Z. was involved in study design and reviewed the manuscript. A.E.P. and M.J.L. provided reagents, performed research and reviewed the manuscript.
Corresponding authorCorrespondence to Neil P. Shah.
Ethics declarations Competing interestsThe following authors declare competing financial interests: C.C.S. (consultancy, Astellas Pharma); M.J.L. (consultancy, Ambit Biosciences); J.P.H. and P.P.Z. (employment, Ambit Biosciences) E.E.S. and A.K. (equity ownership and employment, Pacific Biosciences); C.-S.C., K.J.T. and S.W. (employment, Pacific Biosciences).
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About this articleCite this articleSmith, C., Wang, Q., Chin, C. et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485, 260鈥?63 (2012). https://doi.org/10.1038/nature11016
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Received: 25 August 2011
Accepted: 05 March 2012
Published: 15 April 2012
Issue Date: 10 May 2012
DOI: https://doi.org/10.1038/nature11016
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Editorial SummaryFLT3 a target in leukaemia
Activating internal tandem duplication FLT3 mutations are relatively frequent in acute myeloid leukaemia (AML). Although they are associated with poor prognosis, it has remained unclear whether they play a causal part in the development of AML. In a study of AC220 (quizartinib), an FLT3 kinase inhibitor that is currently being evaluated in clinical trials for people with AML, Neil Shah and colleagues have identified secondary mutations in FLT3 that confer resistance to AC220. The mutations are present in cell lines and in people treated with AC220 who have relapsed after an initial response, and seem to act by preventing FLT3 inhibitor binding. This study establishes FLT3 as a potential target in a subset of AML cases.
