title: Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription.
abstract: Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.
authors.affiliation: Cell Growth and Differentiation Laboratory, Division of Human Immunology, SA Pathology, Adelaide, South Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.forename: Jason A
authors.initials: JA
authors.lastname: Powell
authors.forename: Francois
authors.initials: F
authors.lastname: Vergez
authors.forename: David H
authors.initials: DH
authors.lastname: Segal
authors.forename: Nhu-Y N
authors.initials: NY
authors.lastname: Nguyen
authors.forename: Adele
authors.initials: A
authors.lastname: Baker
authors.forename: Tse-Chieh
authors.initials: TC
authors.lastname: Teh
authors.forename: Emma F
authors.initials: EF
authors.lastname: Barry
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Sarry
authors.forename: Erwin M
authors.initials: EM
authors.lastname: Lee
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Nero
authors.forename: Anissa M
authors.initials: AM
authors.lastname: Jabbour
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pomilio
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Green
authors.forename: Stéphane
authors.initials: S
authors.lastname: Manenti
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Glaser
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ekert
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Susie K
authors.initials: SK
authors.lastname: Nilsson
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Wei
authors.forename: Mark A
authors.initials: MA
authors.lastname: Guthridge
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D006835:Hydrazones / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C549211:PIK 75; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9