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PDK1 Attenuation Fails to Prevent Tumor Formation in PTEN-Deficient Transgenic Mouse Models.

著者 Ellwood-Yen K , Keilhack H , Kunii K , Dolinski B , Connor Y , Hu K , Nagashima K , O'Hare E , Erkul Y , Di Bacco A , Gargano D , Shomer NH , Angagaw M , Leccese E , Andrade P , Hurd M , Shin MK , Vogt TF , Northrup A , Bobkova EV , Kasibhatla S , Bronson
Cancer Res.2011 Apr 15 ; 71(8):3052-3065.
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Authors' Affiliations: Merck Research Laboratories; Harvard Medical School, Boston, Massachusetts; and Merck Research Laboratories, Rahway, New Jersey.

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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. Cancer Res; 71(8); 3052-65. ©2011 AACR.
PMID: 21493594 [PubMed - as supplied by publisher]
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