RNA-based mechanisms underlying oncogenicity and drug resistance in NRG1-rearranged non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), accounting for nearly 85 % of lung tumors, remains one of the most fatal cancers worldwide. Among the various oncogenic drivers identified in NSCLC, neuregulin-1 (NRG1) gene fusions, though rare, occurring in approximately 0.1-0.3 % of cases, are clinically significant, particularly in invasive mucinous adenocarcinomas. These genomic events trigger abnormal heterodimerization of ERBB2 and ERBB3, stimulating downstream PI3K/AKT and MAPK pathways, which in turn foster uncontrolled growth, metastatic potential, and therapeutic resistance. These genomic events cause ERBB2 and ERBB3 to form abnormal heterodimers that activate downstream PI3K/AKT and MAPK signaling pathways, driving uncontrolled growth, metastasis, and therapeutic resistance. Alongside these mechanisms, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of cancer-related networks. Although they do not encode proteins, ncRNAs exert influence at transcriptional, post-transcriptional, and epigenetic levels, with the capacity to either suppress or enhance oncogenic processes. This review examines the interplay between ncRNA activity and NRG1 fusion-driven signaling in NSCLC, highlighting their roles in modulating pathways and contributing to drug resistance. Tumor-suppressive miRNAs, such as miR-22 and miR-296-5p, directly target NRG1 or ERBB2/ERBB3 transcripts, thereby weakening aberrant signaling cascades. Conversely, oncogenic ncRNAs like MALAT1 and HOTAIR facilitate epithelial-mesenchymal transition, cell proliferation, and chemoresistance, while circRNAs amplify oncogenic effects by acting as miRNA sponges. Collectively, these regulatory molecules shape the oncogenic landscape of NRG1-rearranged NSCLC and influence therapeutic outcomes. Dysregulated ncRNAs thus hold promise as biomarkers for diagnosis, prognosis, and treatment planning, with therapeutic strategies aimed at restoring tumor-suppressive ncRNAs or inhibiting oncogenic ones offering a potential avenue to overcome resistance in this subset of patients.