Targetable Gene Fusion Identified in Subset of Triple-Negative Breast Cancers

One of the largest whole-exome sequencing analyses in breast cancer is published this week in Nature, identifying a new gene fusion among a subset of triple-negative breast cancers.[1] The MAGI3–AKT3 fusion results in constant activation of the AKT kinase, part of phosphatidylinositol 3-kinase (PI3K) pathway upregulated in many cancers. The researchers were able to block the activity of the AKT kinase using a specific AKT small-molecule inhibitor, GSK-690693, suggesting the fusion is a potential target for breast cancer therapy.

“The MAGI3–AKT3 translocation and deletion of MAGI3 could result in the combined loss of function of a tumur suppressor gene (PTEN) and activation of an oncogene (AKT3),” said the authors. The identification of the PI3K-pathway driven gene fusion as a new potential druggable target is particularly exciting as it may result in a classification of a subset of triple-negative breast cancers. For now, triple-negative breast cancers are merely classified as such due to a lack of either estrogen receptor or HER2 upregulation-they are a heterogeneous group of cancers that behave differently due to different underlying mutational drivers.

The study is one of several over the last few months in Nature, and one of five published this week, that analyzes the genetic changes of breast cancer cells in order to better understand the biology of the disease and find novel ways to detect and treat breast cancer. Joe Gray and Brian Druker, both of the Knight Cancer Institute at Oregon Health and Science University in Portland, Oregon, in their commentary on these latest genome-wide analyses emphasize the importance of understanding how the mutations identified contribute to tumorigenesis and cancer progression and how the mutations collaborate together to evolve a tumor.[2] “Understanding such deregulated biology should facilitate the development of therapeutic approaches targeting specific cellular pathways, including combination therapies, which are likely to be needed to achieve more durable patient responses,” they wrote in their commentary.

Shantanu Banerji and Matthew Meyerson, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues performed whole-exome sequencing from 103 breast cancers of different subtypes from. The samples, from 54 patients in Mexico and 49 patients in Vietnam were compared to matched, normal DNA samples from people without cancer. The authors analyzed somatic mutations and found the rate of amino acid–changing mutations (nonsilent mutations) of about one mutation per million DNA base pairs.

Screening an additional 235 breast cancer samples uncovered eight samples, including five triple-negative breast cancer samples, that harbored the MAGI3–AKT3 gene fusion.

The study also identified two novel, frequently mutated genes among the breast cancer samples-CBFB and RUNX1. The study also confirmed recurrent somatic mutations in five genes previously found in breast cancer patients-PIK3CA, TP53, AKT1, GATA3, and MAP3K1. Mutations in CBFB were identified, and deletions of the binding partner of CBFB, RUNX1.

CBFB (core-binding factor subunit beta) is a transcription factor that regulates genes including RUNX1 (runt-related transcription factor 1), that function in hematopoiesis and osteogenesis. RUNX1 functions to regulate the transition of hematopoietic stem cells into mature blood cells. Both RUNX1 and CBFB function in the same protein complex and are known to be mutated in acute myeloid leukemia and other types of blood cancers. This the first time either gene has been identified in a breast cancer analysis and the first time CBFB has been found “as a significantly mutated gene in breast cancer,” according to the authors. CBFB was reported in four estrogen-receptor positive samples. The sample size is too small to confirm whether this mutation may be specific to the estrogen-receptor–positive subtype.

An additional gene that was found mutated, but at a frequency below the statistically significant threshold was ERBB2, also known as HER2 (human epidermal growth factor receptor 2). The data suggests that these may be new HER2 mutations that could potentially be targeted with trastuzumab (Herceptin). Currently, the majority of HER2-positive patients who are treated with trastuzumab have amplification of the HER2 gene.

While more research is necessary to validate these new targets, the authors suggest that tumors harboring genomic fusions of AKT3 should be targeted with AKT inhibitors in clinical trials of triple-negative breast cancer patients.

Reference

1. Banerji S, Cibulskis K, Rangel-Escareno C. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;486:405-409.

2. Gray J, Druker B. Genomics: The breast cancer landscape. Nature. 2012;486:328-329.