NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents

Abstract

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents z2%e10% of lung adenocarcinomas and has a reported incidence of z10%e30% for NRG1 fusions. A substantial proportion (z20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.

Phase 1 Dose Escalation Study of Seribantumab (MM-121), an anti-HER3 Monoclonal Antibody, in Patients with Advanced Solid Tumors

“…Fusions of NRG1, the activating ligand of HER3, are rare genomic alterations found in 0.2%-0.5% of all solid tumors and have been identi ed in > 10 unique tumor types [14,15]. Since the completion of this study, our knowledge of NRG1 fusions and their role in HER3 tumor biology has expanded notably, along with the increasing number of NRG1 fusion partners identi ed across multiple solid tumor types [11,16,17]. Per current understanding, HER3 overactivation by NRG1 fusion proteins represents the primary driver of growth and survival in tumors harboring NRG1 fusions [16][17][18], and the presence (vs. absence) of NRG1 fusions has been shown to correlate with worsened survival outcomes in lung cancer, including shorter overall survival and disease-free survival [19].…”

Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D‐NRG1 gene fusion in prostate cancer by data‐drilling a de‐identified tumor database

“…Previously, in vitro studies have shown that NRG1 fusion genes are oncogenic drivers, and NRG1 rearranged carcinomas could be sensitive to the ERBB2 and the new generation of ERBB3 targeting therapies 15,27,28 . Currently, dozens of molecules aiming at ERBB2 and ERBB3 are being clinically tested 24,28‐31 . Thus, it is worth identifying the patients with NRG1 fusion carcinomas providing them with the pathway to targeted therapy.…”

“…The screening strategy is not established so far. NRG1 rearranged tumors are enriched (reportedly 7%‐31%) in lung invasive mucinous adenocarcinomas followed by pancreatobiliary system, ovary, breast, and rare findings in other locations 8,21,25,26,31‐34 . Possibly, lung (invasive mucinous) adenocarcinomas or less specifically NSCLC could be the most suitable for starting a routine NRG1 rearrangement testing followed by the other organ sites including pancreas and prostate 20,30 .…”

“…15,27,28 Currently, dozens of molecules aiming at ERBB2 and ERBB3 are being clinically tested. 24,[28][29][30][31] Thus, it is worth identifying the patients with NRG1 fusion carcinomas providing them with the pathway to targeted therapy. The screening strategy is not established so far.…”

“…NRG1 rearranged tumors are enriched (reportedly 7%-31%) in lung invasive mucinous adenocarcinomas followed by pancreatobiliary system, ovary, breast, and rare findings in other locations. 8,21,25,26,[31][32][33][34] Possibly, lung (invasive mucinous) adenocarcinomas or less specifically NSCLC could be the most suitable for starting a routine NRG1 rearrangement testing followed by the other organ sites including pancreas and prostate. 20,30 So far, majority (over 90%) of NRG1 rearranged carcinomas described by respectful studies showed KRAS and BRAF wildtype phenotype including pancreatic cancer 22 and NSCLCs.…”