AKT3

Overview

AKT3 encodes a serine/threonine protein kinase that is a member of the AKT/PKB family and a downstream effector of PI3K signaling. In triple-negative breast cancer, AKT3 is activated through a recurrent gene fusion (MAGI3-AKT3) that produces constitutive kinase activity independent of upstream PI3K or PTEN regulation. Unlike AKT1 point mutations (E17K), the fusion mechanism has distinct pharmacological implications for targeted therapy selection.

Alterations observed in the corpus

  • MAGI3-AKT3 gene fusion (intron 1 breakpoint) identified in breast cancer WES/WGS of 103 tumors (Broad Institute); fusion is enriched in triple-negative breast cancer and produces constitutive AKT phosphorylation PMID:22722202
  • Mutated in TCGA lung squamous cell carcinoma cohort (178 tumors), identified as part of broad genomic characterization PMID:22960745
  • Recurrently altered across endometrial carcinoma subtypes in the ucec_tcga_pub TCGA cohort; identified in mutation panel analyses (Fig. 2d/Fig. 5b) PMID:23636398
  • Overexpression observed in 10% of muscle-invasive bladder carcinomas (BLCA); part of the PI(3)K/AKT/mTOR pathway altered in 42% of tumours, representing a potential therapeutic target with AKT inhibitors PMID:24476821
  • Amplification, overexpression, and recurrent fusions (CEP170-AKT3, AKT3-PLD5, ZEB2-AKT3, ARHGAP30-AKT3) enriched in RAS/NF1/Triple-WT melanoma subtypes vs BRAF (p < 0.05); E17K mutation nominated as biomarker for MEK + PI3K/AKT/mTOR combination therapy PMID:26091043
  • AKT3 mutation identified as part of the PI3K/AKT/mTOR pathway gene set disrupted in 39% of anaplastic thyroid carcinomas (ATC) vs 11% of poorly differentiated thyroid carcinomas (PDTC) (P = 1×10⁻³) in a 341-gene targeted sequencing cohort (n=117 advanced tumors) PMID:26878173
  • AKT3 carries activating hotspot mutations alongside AKT1, PIK3CA, and PIK3R1 in prostate cancer; combined PI3K/AKT pathway alterations nominate PI3K-pathway inhibitors as candidates PMID:28825054
  • PI3K/AKT/MTOR pathway alterations occur in 84% of ULMS+STLMS C1 vs 44% of STLMS C2 sarcomas; AKT3 is among the pathway components with recurrent alterations nominating dual PI3K/MTOR or TORC1/TORC2 inhibitors PMID:29100075

Cancer types (linked)

  • Breast cancer (BRCA): MAGI3-AKT3 fusion detected in triple-negative subtype; constitutive Akt activation bypasses PI3K-level regulation PMID:22722202

Co-occurrence and mutual exclusivity

  • MAGI3-AKT3 fusion co-occurs with hemizygous MAGI3 deletion, resulting in complete loss of the MAGI3 PTEN-binding PDZ domain PMID:22722202

Therapeutic relevance

  • Constitutive AKT3 activation via MAGI3-AKT3 fusion is inhibited by ATP-competitive AKT inhibitor GSK-690693 but NOT by allosteric PH-domain inhibitor MK-2206; fusion-positive triple-negative breast cancers should be treated with ATP-competitive (not allosteric) AKT inhibitors PMID:22722202

Open questions

  • The frequency of MAGI3-AKT3 fusions in broader breast cancer cohorts (beyond the 103-tumor Broad study) and their prevalence across triple-negative subtypes remain to be characterized PMID:22722202

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:22960745

This page was processed by crosslinker on 2026-05-14. - PMID:23636398

This page was processed by crosslinker on 2026-05-14. - PMID:24476821

This page was processed by crosslinker on 2026-05-14. - PMID:26091043

This page was processed by crosslinker on 2026-05-14. - PMID:26878173

This page was processed by entity-page-writer on 2026-05-15.