title: Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation.
abstract: Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD(+) AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.
authors.affiliation: Departments of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Cheuk Him
authors.initials: CH
authors.lastname: Man
authors.forename: Tsz Kan
authors.initials: TK
authors.lastname: Fung
authors.forename: Christa
authors.initials: C
authors.lastname: Ho
authors.forename: Heron H C
authors.initials: HH
authors.lastname: Han
authors.forename: Howard C H
authors.initials: HC
authors.lastname: Chow
authors.forename: Alvin C H
authors.initials: AC
authors.lastname: Ma
authors.forename: William W L
authors.initials: WW
authors.lastname: Choi
authors.forename: Si
authors.initials: S
authors.lastname: Lok
authors.forename: Alice M S
authors.initials: AM
authors.lastname: Cheung
authors.forename: Connie
authors.initials: C
authors.lastname: Eaves
authors.forename: Yok Lam
authors.initials: YL
authors.lastname: Kwong
authors.forename: Anskar Y H
authors.initials: AY
authors.lastname: Leung
mesh_terms: D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects; D001853:Bone Marrow / Q000201:enzymology / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053616:Janus Kinase 3 / Q000096:biosynthesis / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D053517:Matrix Metalloproteinase 15 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D050697:Retinal Dehydrogenase; D000077157:Sorafenib; D013997:Time Factors; D014183:Transplantation, Heterologous; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C507098:MMP15 protein, human; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D053517:Matrix Metalloproteinase 15