Rescue of Proteus syndrome lethality in mice with prenatal miransertib treatment.

PURPOSE: Proteus syndrome is caused by constitutive AKT1 activation, resulting in severe overgrowth and tumor susceptibility. We developed a mouse model, featuring endogenously regulated, mosaic expression of the Akt1 c.49G>A, p.(Glu17Lys) (Akt1 E17K) variant. Prior results showed that ubiquitous Akt1E17K expression causes embryonic lethality. We hypothesized that a therapeutic effect of a small molecule could rescue the embryonic lethality and serve as a screen for the therapeutic potential of an agent. METHODS: We first tested whether miransertib, an allosteric pan-AKT inhibitor can cross the placental barrier. To assess embryonic survival to birth, dams from timed matings between ACTB-Cre and Akt1WT/flx mice were dosed at specific gestational time points. RESULTS: Mice treated at 60 or 90 mg/kg/day showed a significantly increased, p=0.0003, proportion of neonatal survival (15/63 compared to 6/152). A startling observation was that several mutant βA-Akt1WT/flx mice were not only born alive but were apparently healthy until nearly 18 months of age without postnatal miransertib treatment and showed a high variant allele fraction in nearly all tissues. CONCLUSION: Dose-dependent rescue of βA-Akt1WT/flx embryos using miransertib validates the drug's potential as a therapeutic candidate. The βA-Akt1WT/flx mouse model can serve as a platform for rapid preclinical drug testing for Proteus syndrome.