NRG1 : A Cinderella Fusion in Lung Cancer?

Abstract

The amazing bridge between gene fusions and lung cancer has been greatly consolidated during the last decades. The identification of ALK and ROS1 rearrangements gives the great opportunity to rewrite the standard-of-care for a portion of advanced non-small-cell lung cancer (NSCLC) patients. Despite their very low incidence, these well-known genomic rearrangements share common features strictly associated to specific phenotypes of lung adenocarcinoma. This makes them ideal for diagnostic procedures, patients' stratification and therapies [1,2]. In this scenario, the finding of further intriguing targetable gene fusions, despite with a low incidence (1-2%) in NSCLC, is now increasing and it is watched with attention by the clinical community [3]. Recently, the NRG1 gene has been described as a new molecular feature of NSCLC [4]. The NRG1 gene is located at the long arm of chromosome 10 (10q23.1 region) and 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 [5]. The neuronal isoform NRG1 III-β3 is generally not expressed in normal lung tissue, but it was found to be ectopically activated in lung tumor cells by NRG1 genomic rearrangements involving mainly CD74 and SLC3A2 genes [6]. It is the first fusion associated with the mucinous subtype of lung adenocarcinoma with an occurrence ranging from 8 to 27%. By contrast, NRG1-gene fusions occur in 1-2% of NSCLC and occasionally reported in other solid tumors [7]. It has been more extensively investigated in Asian than Caucasian lung cancer patients in whom it has been not yet fully elucidated and remains only partially understood [6]. ERBB signaling is one of the most deregulated lung cancer cascades. ERBB3 is not frequently affected by mutations or amplifications in lung cancer. Furthermore, MET or HER2 amplifications, which represent additional mechanisms of ERBB3 activation in lung tumors, rarely occur. Thus, the overproduction of NRG1 ligands could represent one of the leading mechanisms by which lung cancer cells aberrantly activate ERBB3-related receptor tyrosine kinase signaling. The first suggestion of a real clinical utility of NRG1 fusion comes by analyzing a large sample of mucinous lung adenocarcinoma in Asians for the NRG1 breaks. In fact, patients with stage I disease harboring tumors with NRG1 fusions showed an inferior overall survival and a trend toward a shorter disease-free survival compared with those without NRG1 fusions [8]. The powerfulness of this fusion has been highlighted in vitro. In fact, the expression of CD74-NRG1 fusion gene is able to promote cancer stem cell properties and it is involved in stem cell function of several types of cancers, including lung cancer. These data imply the existence of a mechanism by which the activated ERBB receptors contribute to the acquisition of cancer stem cell-like characteristics together with the ability of cancer cells to develop a resistance to chemotherapy [9]. Moreover, in the absence of RAS pathway