What is Rare NRG1 fusion?

The neuregulin-1 (NRG1) gene encodes for the neuregulin 1, a growth factor belonging to the complex family of proteins also called heregulins. These proteins are structurally related to the stimulation of ERBB receptors tyrosine kinase activity and EGF signals. Specifically, the NRG1-receptor binding induces the phosphorylation of the intrinsic kinase domains of ERBB3 and stimulates its dimerization with ERBB2 receptor and the activation of the downstream PI3K-AKT and MAPK pathways. NRG1 fusions are a rare but powerful oncogene driver that makes cancer particularly aggressively and deadly when it is present. Therefore, they have emerged as a potential therapeutic target across multiple tumor types.

Gene fusions occur when two previously independent genes connect, producing increased amounts of abnormal protein that trigger and fuel tumor growth. Rare NRG1 fusions are rare but recurrent oncogenic drivers occurring in ~0.2% of solid tumors and enriched in certain tumor subtypes such as the invasive mucinous adenocarcinoma subtype of the lung. There are many types of NRG1 fusions, involving different genes, and they are a culprit in many cancers with poor survival rates, such as lung cancers among patients who never smoked and pancreatic cancer.

The specific NRG1 fusion partners are variable within and across tumor types. The most common NRG1 fusion partners include CD74, SLC3A2, SDC, and others. Several fusion partners identified in lung cancers include ATP1B1, SDC4, RBPMS, TNC, MRPL13, MDK and DIP2B. The gold standard for detection of NRG1 gene fusions is RNA sequencing in comparison with DNA sequencing, although fluorescence in situ hybridization (FISH) can be used as a pre-screening method for its detection, but only genetic sequencing will allow the identification of the gene fusions.

There are currently no approved treatments targeted towards treating cancers caused by NRG1 Fusions. The standard strategies for treating patients with advanced solid tumors that are NRG1 fusion–positive are chemo-immunotherapy or novel anti–PD-1 or anti–PD-L1 agents. Certain studies with results show that afatinib, seribantumab, zenocutuzumab and others have the potential for the effective treatment of NRG1 Fusion. Several clinical reports have demonstrated that NRG1 fusions are a viable, actionable target in tumors, with responses seen on inhibition of ERBB family members.

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