title: Context-dependent antagonism between Akt inhibitors and topoisomerase poisons.
abstract: Signaling through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which is aberrantly activated in >50% of carcinomas, inhibits apoptosis and contributes to drug resistance. Accordingly, several Akt inhibitors are currently undergoing preclinical or early clinical testing. To examine the effect of Akt inhibition on the activity of multiple widely used classes of antineoplastic agents, human cancer cell lines were treated with the Akt inhibitor A-443654 [(2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan-2-amine; ATP-competitive] or MK-2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride; allosteric inhibitor) or with small interfering RNA (siRNA) targeting phosphoinositide-dependent kinase 1 (PDK1) along with cisplatin, melphalan, camptothecin, or etoposide and assayed for colony formation. Surprisingly different results were observed when Akt inhibitors were combined with different drugs. Synergistic effects were observed in multiple cell lines independent of PI3K pathway status when A-443654 or MK-2206 was combined with the DNA cross-linking agents cisplatin or melphalan. In contrast, effects of the Akt inhibitors in combination with camptothecin or etoposide were more complicated. In HCT116 and DLD1 cells, which harbor activating PI3KCA mutations, A-443654 over a broad concentration range enhanced the effects of camptothecin or etoposide. In contrast, in cell lines lacking activating PI3KCA mutations, partial inhibition of Akt signaling synergized with camptothecin or etoposide, but higher A-443654 or MK-2206 concentrations (>80% inhibition of Akt signaling) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis, a process that contributes to effective DNA damage and killing by these agents. These results indicate that the effects of combining inhibitors of the PI3K/Akt pathway with certain classes of chemotherapeutic agents might be more complicated than previously recognized.
authors.affiliation: Divisions of Oncology Research (M.G.-P., K.S.F., D.A.L., K.L.P., P.A.S., S.H.K.) and Medical Oncology (C.E.), Department of Oncology and Department of Molecular Pharmacology & Experimental Therapeutics (S.H.K.), Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Marina
authors.initials: M
authors.lastname: Gálvez-Peralta
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.forename: David A
authors.initials: DA
authors.lastname: Loegering
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D045325:HCT116 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011042:Poisons / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000378:metabolism / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C504035:A 443654; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D007191:Indazoles; D007211:Indoles; C548887:MK 2206; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011042:Poisons; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt