title: Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia.
abstract: OBJECTIVE
  Recent studies suggested that AKT activation might confer poor prognosis in acute myelogenous leukemia (AML), providing the rationale for therapeutic targeting of this signaling pathway. We, therefore, explored the preclinical and clinical anti-AML activity of an oral AKT inhibitor, MK-2206. Experimental Methods: We first studied the effects of MK-2206 in human AML cell lines and primary AML specimens in vitro. Subsequently, we conducted a phase II trial of MK-2206 (200 mg weekly) in adults requiring second salvage therapy for relapsed/refractory AML, and assessed target inhibition via reverse phase protein array (RPPA).
  
  
  RESULTS
  In preclinical studies, MK-2206 dose-dependently inhibited growth and induced apoptosis in AML cell lines and primary AML blasts. We then treated 19 patients with MK-2206 but, among 18 evaluable participants, observed only 1 (95% confidence interval, 0%-17%) response (complete remission with incomplete platelet count recovery), leading to early study termination. The most common grade 3/4 drug-related toxicity was a pruritic rash in 6 of 18 patients. Nevertheless, despite the use of MK-2206 at maximum tolerated doses, RPPA analyses indicated only modest decreases in Ser473 AKT (median 28%; range, 12%-45%) and limited inhibition of downstream targets.
  
  
  CONCLUSIONS
  Although preclinical activity of MK-2206 can be demonstrated, this inhibitor has insufficient clinical antileukemia activity when given alone at tolerated doses, and alternative approaches to block AKT signaling should be explored.
authors.affiliation: Authors' Affiliations: Department of Leukemia; Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Hematology/Department of Medicine; Department of Epidemiology, University of Washington, Seattle, Washington; and National Cancer Institute, Rockville, Maryland.
authors.forename: Marina Y
authors.initials: MY
authors.lastname: Konopleva
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Faderl
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Jabbour
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zeng
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.forename: Tapan M
authors.initials: TM
authors.lastname: Kadia
authors.forename: Peter P
authors.initials: PP
authors.lastname: Ruvolo
authors.forename: Jennie B
authors.initials: JB
authors.lastname: Feliu
authors.forename: Hongbo
authors.initials: H
authors.lastname: Lu
authors.forename: Lakiesha
authors.initials: L
authors.lastname: Debose
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liu
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.forename: Elihu H
authors.initials: EH
authors.lastname: Estey
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D018922:HL-60 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D015151:Immunoblotting; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011537:Pruritus / Q000139:chemically induced; D016879:Salvage Therapy / Q000379:methods*; D016896:Treatment Outcome; D020298:U937 Cells
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D051057:Proto-Oncogene Proteins c-akt