title: Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects.
abstract: Targeting the phosphatidylinositol-3-kinase (PI3K) is a promising approach in cancer therapy. In particular, PI3K blockade leads to the inhibition of AKT, a major downstream effector responsible for the oncogenic activity of PI3K. However, we report here that small molecule inhibitors of PI3K only transiently block AKT signaling. Indeed, treatment of cancer cells with PI3K inhibitors results in a rapid inhibition of AKT phosphorylation and signaling which is followed by the reactivation of AKT signaling after 48 h as observed by Western blot. Reactivation of AKT signaling occurs despite effective inhibition of PI3K activity by PI3K inhibitors. In addition, wortmannin, a broad range PI3K inhibitor, did not block AKT reactivation suggesting that AKT signals independently of PI3K. In a therapeutical perspective, combining AKT and PI3K inhibitors exhibit stronger anti-proliferative and pro-apoptotic effects compared to AKT or PI3K inhibitors alone. Similarly, in a tumor xenograft mouse model, concomitant PI3K and AKT blockade results in stronger anti-cancer activity compared with either blockade alone. This study shows that PI3K inhibitors only transiently inhibit AKT which limits their antitumor activities. It also provides the proof of concept to combine PI3K inhibitors with AKT inhibitors in cancer therapy.
authors.affiliation: Department of Visceral Surgery, Lausanne University Hospital, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Dufour
authors.forename: Anne
authors.initials: A
authors.lastname: Dormond-Meuwly
authors.forename: Catherine
authors.initials: C
authors.lastname: Pythoud
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demartines
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D000077191:Wortmannin
keywords: AKT; Cancer; PI3K; PI3K inhibitors; PTEN; Resistance; Signaling; phosphatase and tensin homolog; phosphatidylinositol-3-kinase