title: In vivo activity of combined PI3K/mTOR and MEK inhibition in a Kras(G12D);Pten deletion mouse model of ovarian cancer.
abstract: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by Kras(G12D) activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% ± 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogen-activated protein kinase pathway downstream of Kras(G12D) expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras.
authors.affiliation: Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, Australia. kathryn.kinross@petermac.org
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kinross
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Brown
authors.forename: Margarete
authors.initials: M
authors.lastname: Kleinschmidt
authors.forename: Susan
authors.initials: S
authors.lastname: Jackson
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase; D018631:ras Proteins; D005947:Glucose