Gene fusions are genomic alterations that can drive cancer. These fusions occur when two previously separate genes, or parts of them, join, creating a new gene. Those involving the Neuregulin 1 (NRG1) gene are a rare genomic change found across various solid tumors. Understanding NRG1 fusions provides insight into how these errors contribute to uncontrolled cell growth, enabling precise treatment strategies.
The Biology of NRG1 Gene Fusions
The NRG1 gene produces neuregulin proteins, which play a role in cell growth and development. These neuregulins act as signaling molecules, interacting with ErbB (HER) family receptors on the cell surface, such as ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). This interaction helps regulate normal cell functions.
An NRG1 gene fusion occurs when a segment of NRG1 attaches to another gene, creating a new, hybrid gene. This hybrid gene produces an abnormal “fusion protein” containing the active Epidermal Growth Factor (EGF)-like domain of NRG1. This protein is often tethered to the cell surface or improperly regulated.
The presence of this fusion protein causes the ErbB receptors to become abnormally and continuously activated. This is similar to a light switch being permanently stuck in the “on” position, leading to constant signaling for cell growth and division. This sustained activation of pathways like PI3K-AKT and MAPK promotes uncontrolled cell proliferation and tumor formation.
Associated Cancer Types
NRG1 gene fusions are identified across a spectrum of solid tumors and are generally uncommon. Non-small cell lung cancer (NSCLC) is the most frequently observed, accounting for approximately 54% of identified NRG1 fusions. Within NSCLC, these fusions are noted in invasive mucinous adenocarcinomas (IMA), with an incidence of 10% to 30%.
Beyond lung cancer, NRG1 fusions have also been found in pancreatic cancer and cholangiocarcinoma (bile duct cancer), with an incidence of less than 1%. Other detected cancer types include breast, ovarian, colorectal, and renal cell carcinoma. Identifying an NRG1 fusion in a patient’s tumor is important because it indicates a specific molecular vulnerability that can be targeted with specialized therapies.
Detection and Diagnostic Methods
Detecting an NRG1 gene fusion requires advanced molecular diagnostic techniques. The primary method for comprehensive genomic profiling is Next-Generation Sequencing (NGS). NGS reads the genetic code within a tumor’s DNA or RNA to pinpoint specific alterations, such as gene fusions, that might be driving the cancer.
RNA-based NGS is more reliable for detecting NRG1 fusions compared to DNA-based methods. This is because the NRG1 gene has large non-coding regions, and fusions can occur in complex ways, making RNA analysis more effective at identifying the functional fusion product. RNA sequencing can also detect unknown fusion partners, given the diversity of genes that can fuse with NRG1.
While NGS is the preferred method, other techniques like Immunohistochemistry (IHC) or Fluorescence In Situ Hybridization (FISH) have also been used. IHC can detect the abnormal proteins produced by fusions, while FISH can visualize chromosomal rearrangements. These methods offer different insights, but NGS provides more comprehensive and precise identification of these complex genetic changes.
Targeted Therapy Approaches
The discovery of NRG1 fusions has opened avenues for targeted therapy, a form of precision medicine that blocks the cancer-driving mechanism rather than broadly attacking fast-growing cells. Since NRG1 fusions aberrantly activate the ErbB/HER pathway, drugs inhibiting this pathway can be effective. These therapies aim to “turn off” the constantly active growth signal initiated by the fusion protein.
Pan-ErbB tyrosine kinase inhibitors are effective drugs that block the activity of multiple ErbB receptors. Afatinib, for instance, is an irreversible pan-ErbB inhibitor demonstrating responses in patients with NRG1 fusion-positive cancers, including lung adenocarcinoma, pancreatic ductal adenocarcinoma, ovarian cancer, and cholangiocarcinoma. It works by binding to and inhibiting the kinase domains of ErbB1, ErbB2, and ErbB4, thereby downregulating the abnormal signaling.
Other investigational drugs are being explored. Seribantumab, a humanized monoclonal antibody, targets the HER3 receptor, preventing NRG1 from binding and inhibiting subsequent activation of signaling pathways like PI3K/AKT. Zenocutuzumab, a bispecific antibody, employs a “dock and block” mechanism by binding to HER2 and preventing HER3 from interacting with NRG1 fusion proteins, disrupting the growth signals. These targeted approaches offer tailored treatment options for patients whose cancers are driven by these genetic alterations.