Neuregulin 1 Gene (NRG1). A Potentially New Targetable Alteration for the Treatment of Lung Cancer.

Abstract

Simple SummaryTreatment in oncology has and will keep evolving into an agnostic approach where therapies are guided more towards the identification and targeting of genetic abnormalities and less by organ of origin of the cancer, as has been done for decades. With every genetic abnormality being identified as a target, the pharmaceutical development of medications targeting these genes has grown, leading to better survival rates, quality of life and a bigger interest in finding new targets. Lung cancer is one of the best examples where targetable genetic abnormalities have led to substantial survival differences compared to patients undergoing empirical conventional chemotherapy. Translocations in the neuregulin 1 gene (NRG1) are one of many gene fusions that are becoming clinically significant, and it has the potential to become a targetable gene with ongoing clinical trials already in Europe and the US. This review aims to portray the importance and latest developments regarding this new fusion in lung cancer treatment.Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to unregulated cell proliferation by different mechanisms in a wide variety of cancer. This has led to the development of directed therapies to antagonize a variety of mechanisms that lead to cell growth or proliferation. Multiple oncogene fusions are currently targeted in lung cancer treatment, such as those involving ALK, RET, NTRK and ROS1 among many others. Neuregulin (NRG) gene fusion has been described in the development of normal tissue as well as in a variety of diseases, such as schizophrenia, Hirschsprung’s disease, atrial fibrillation and, most recently, the development of various types of solid tumors, such as renal, gastric, pancreatic, breast, colorectal and, more recently, lung cancer. The mechanism for this is that the NRG1 chimeric ligand leads to aberrant activation of ERBB2 signaling via PI3K-AKT and MAPK cellular cascades, leading to cell division and proliferation. Details regarding the incidence of these gene rearrangements are lacking. Limited case reports and case series have evaluated their clinicopathologic features and prognostic significance in the lung cancer population. Taking this into account, NRG1 could become a targetable alteration in selected patients. This review highlights how the knowledge of new molecular mechanisms of NRG1 fusion may help in gaining new insights into the molecular status of lung cancer patients and unveil a novel targetable molecular marker.