title: PDK1 attenuation fails to prevent tumor formation in PTEN-deficient transgenic mouse models.
abstract: PDK1 activates AKT suggesting that PDK1 inhibition might suppress tumor development. However, while PDK1 has been investigated intensively as an oncology target, selective inhibitors suitable for in vivo studies have remained elusive. In this study we present the results of in vivo PDK1 inhibition through a universally applicable RNAi approach for functional drug target validation in oncogenic pathway contexts. This approach, which relies on doxycycline-inducible shRNA expression from the Rosa26 locus, is ideal for functional studies of genes like PDK1 where constitutive mouse models lead to strong developmental phenotypes or embryonic lethality. We achieved more than 90% PDK1 knockdown in vivo, a level sufficient to impact physiological functions resulting in hyperinsulinemia and hyperglycemia. This phenotype was reversible on PDK1 reexpression. Unexpectedly, long-term PDK1 knockdown revealed a lack of potent antitumor efficacy in 3 different mouse models of PTEN-deficient cancer. Thus, despite efficient PDK1 knockdown, inhibition of the PI3K pathway was marginal suggesting that PDK1 was not a rate limiting factor. Ex vivo analysis of pharmacological inhibitors revealed that AKT and mTOR inhibitors undergoing clinical development are more effective than PDK1 inhibitors at blocking activated PI3K pathway signaling. Taken together our findings weaken the widely held expectation that PDK1 represents an appealing oncology target.
authors.affiliation: Merck Research Laboratories, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Katharine
authors.initials: K
authors.lastname: Ellwood-Yen
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
authors.forename: Kaiko
authors.initials: K
authors.lastname: Kunii
authors.forename: Brian
authors.initials: B
authors.lastname: Dolinski
authors.forename: Yamicia
authors.initials: Y
authors.lastname: Connor
authors.forename: Kun
authors.initials: K
authors.lastname: Hu
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nagashima
authors.forename: Erin
authors.initials: E
authors.lastname: O'Hare
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Erkul
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Bacco
authors.forename: Diana
authors.initials: D
authors.lastname: Gargano
authors.forename: Nirah H
authors.initials: NH
authors.lastname: Shomer
authors.forename: Minilik
authors.initials: M
authors.lastname: Angagaw
authors.forename: Erica
authors.initials: E
authors.lastname: Leccese
authors.forename: Paula
authors.initials: P
authors.lastname: Andrade
authors.forename: Melissa
authors.initials: M
authors.lastname: Hurd
authors.forename: Myung K
authors.initials: MK
authors.lastname: Shin
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Vogt
authors.forename: Alan
authors.initials: A
authors.lastname: Northrup
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Bobkova
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Martin L
authors.initials: ML
authors.lastname: Scott
authors.forename: Giulio
authors.initials: G
authors.lastname: Draetta
authors.forename: Victoria
authors.initials: V
authors.lastname: Richon
authors.forename: Nancy
authors.initials: N
authors.lastname: Kohl
authors.forename: Peter
authors.initials: P
authors.lastname: Blume-Jensen
authors.forename: Jannik N
authors.initials: JN
authors.lastname: Andersen
authors.forename: Manfred
authors.initials: M
authors.lastname: Kraus
mesh_terms: D000818:Animals; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D007942:Leukemia, Experimental / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference
chemical_list: C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse