Abstract 188: Isoform-specific AKT functions in thyroid carcinoma development

Abstract

Abstract Mammalian cells contain three genes that encode three AKT isoforms (AKT1-3). The three genes have >85% sequence identity, and possess conserved threonine and serine residues that are critical for full activation. All AKT isoforms seem to have identical or similar substrate specificity, and it is not clear whether they possess different functional specificities in vivo. Using conditional, organ-specific isoform deletion in a model of PI3K-dependent neoplastic transformation and progression, we are dissecting the molecular and biological roles of AKT1 and AKT2. Thyroid-specific deletion of Pten (Ptenthy-/− mice) results in thyroid hyperplasia at birth which then slowly progresses to solid nodular lesions and finally to invasive carcinomas. Simultaneous thyroid-specific deletion of Akt1 and/or Akt2 demonstrates that both AKT1 and AKT2 are necessary to confer proliferative ability to Pten−/- thyrocytes in an additive manner. However, with age, (Pten,Akt1)thy-/− mice have a significantly higher incidence of thyroid lesions compared to (Pten,Akt2)thy-/− mice. In addition, deletion of Akt2 is more effective than that of Akt1 to extend survival and reduce lesion aggressiveness in Ptenthy-/−/KrasG12D mice. Transcriptomic and proteomic analyses have revealed that AKT2 loss rescues most of the expression and activation changes induced, in vivo, by Pten deletion, while AKT1 loss has more restricted effects. Futhermore we have identified and are characterizing subsets of genes that are differentially regulated by AKT isoforms. These data point to the existence of dramatically different molecular pathways associated with each AKT isoform in the thyroid, and represent a strong rationale for the development of less toxic, more effective treatments based on isoform-specific inhibitors. Citation Format: Michela Ranieri, Antonio Di Cristofano. Isoform-specific AKT functions in thyroid carcinoma development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 188.