MAGI3

Overview

MAGI3 (Membrane Associated Guanylate Kinase, WW And PDZ Domain Containing 3) is a scaffold protein containing PDZ domains, one of which binds PTEN and is required for PTEN-mediated inhibition of PI3K signalling. In triple-negative breast cancer, MAGI3 is disrupted by a recurrent gene fusion with AKT3, producing constitutive AKT activation. Hemizygous deletion of MAGI3 also removes the PTEN-binding PDZ domain, functionally mimicking PTEN loss.

Alterations observed in the corpus

  • MAGI3-AKT3 fusion identified in triple-negative breast cancer (Broad WES/WGS, 103 tumors); hemizygous deletion removes PTEN-binding PDZ domain, producing constitutive AKT activation; fusion enriched in triple-negative subtype (6.9% by RT-PCR in 72 samples) PMID:22722202

Cancer types (linked)

  • TNBC: MAGI3-AKT3 fusion found in ~6.9% of triple-negative breast cancers; fusion produces constitutive AKT phosphorylation and functional PI3K pathway activation PMID:22722202

Co-occurrence and mutual exclusivity

  • MAGI3 disruption leads to functional PTEN loss via loss of the PTEN-binding PDZ domain; represents an alternative mechanism of PI3K pathway activation in tumors without canonical PTEN mutation PMID:22722202

Therapeutic relevance

  • The MAGI3-AKT3 fusion produces constitutive AKT phosphorylation 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

  • Frequency of MAGI3-AKT3 fusion in broader, ethnically diverse cohorts needs validation; current data are from a Mexican/Vietnamese cohort (n=72 for RT-PCR screen) PMID:22722202
  • Functional validation of MAGI3 loss-of-function as a standalone tumorigenic mechanism not yet performed.

Sources

  • PMID:22722202 — Breast cancer WES/WGS, 103 tumors, Broad cohort; PIK3CA/AKT pathway study.

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