Abstract 549: MAGI3-Akt3, a novel fusion protein in the PI 3-K pathway in cancer.

Abstract

Abstract Aberrant activation of the PI3-K/Akt pathway is found in approximately 70% of breast cancers. We recently identified a recurrent rearrangement that produces an in-frame fusion protein containing Akt3 and the scaffolding protein MAGI3 (1). MAGI3-Akt3 is the first fusion protein that has been identified in the PI 3-K pathway. We propose that MAGI3-Akt3 is a novel oncogene in breast cancer and that the oncogenic activity of the fusion protein results from disruption of the PI 3-K/Akt pathway. Within the fusion, Akt3 has a disrupted PH domain prior to glutamate 17 (E17). As a result the fusion protein is constitutively phosphorylated in the Akt3 kinase domain and expression of MAGI3-Akt3 in breast cancer cells enhances Akt substrate phosphorylation. Constitutive MAGI3-Akt3 kinase activity can be inhibited by ATP-competitive small molecule Akt inhibitors but is resistant to the allosteric Akt inhibitor MK2206 which is currently in phase II clinical trials. Our results indicate that ATP competitive Akt inhibitors should be evaluated in clinical trials for the treatment of fusion-positive breast cancers. The fusion protein also contains a severely truncated portion of the scaffolding protein MAGI3. In particular, the fusion lacks the second PDZ domain of MAGI3 that has been reported to bind to PTEN and be required for the inhibitory effect of PTEN on PI 3-K pathway activity. We have demonstrated that disruption of MAGI3 in breast cancer cell lines does indeed promote PI 3-K pathway hyperactivity in a PTEN-dependent manner. In addition, the fusion lacks the fifth PDZ domain of MAGI3 and our studies indicate that this disrupts the interaction of MAGI3 with PHLPP2, a phosphatase that directly dephosphorylates Akt at pS473. Our studies therefore demonstrate that the MAGI3-Akt3 translocation significantly perturbs PI 3-K pathway activity via activation of an oncogene (Akt3) and dysregulation of two tumor suppressors (PTEN and PHLPP2). We are currently continuing studies to elucidate the oncogenic mechanism(s) of MAGI3-Akt3 in breast cancer. Citation Format: Kristin Brown, Alex Toker. MAGI3-Akt3, a novel fusion protein in the PI 3-K pathway in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 549. doi:10.1158/1538-7445.AM2013-549