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 ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) 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.

Keywords: ErbB-targeted treatment; NRG1; afatinib; gene fusion; invasive mucinous adenocarcinoma; non-small-cell lung cancer.

Figure 1:. Mechanism of action figure

Figure 1A. NRG1-fusion proteins drive tumorigenic signaling pathways (adapted from Fernandez-Cuesta and Thomas, 2015, Ferrer et al 2018, Gille et al 1996, Populo et al 2012, Sakatomoto et al 2009, Shi et al 2007, Yang et al 1995, Manning and Cantley, 2007) and common NRG1-fusions (redrawn from Jonna et al 2019). A. Wild type NRG1 may be cleaved by proteases to release soluble NRG1 containing the EGF-like region. Soluble NRG1 diffuses to activate distant ErbB3 or ErbB4 receptor subunits (paracrine signaling). Activated receptors dimerize, forming ErbB3- or ErbB4-containing homo- or hetero ErbB dimers, preferentially involving ErbB2. B. NRG1 fusions by losing, altering or misplacing cleavage sites may become poorer substrates for proteases, e.g. ADAM17, resulting in excess NRG1 tethered to the cell surface. C. NRG1-fusion proteins hold the EGF-like domain close to the cell surface, causing uncontrolled juxtacrine signaling. Aberrant NRG1 signaling drives cell proliferation and avoidance of apoptosis via PI3K and RAS dependent signaling and activation of downstream signalling molecules, including RALBP-1, CREB, ELK-1, 4EBP, S6K and NFκB. D. NRG1-fusion proteins may also drive autocrine signaling via the same PI3K/Ras dependent pathways. Figure 1B. Common NRG1-fusions (redrawn from Jonna et al 2019). Schematics of the wild-type NRG1 gene (green border) and the most common NRG1-fusions (red border, from 21,858 tumours, of more than 26 different types). The CD74-NRG1 fusions shown are CD74 exon 6; CD74 (exon 8)-NRG1 fusions were also reported. The dotted line indicates the point at which NRG1 and the fusion partner are joined. The EGF-like region is shown in purple.

Figure 2:. Incidence of NRG1 fusions in cancer

CRC = colorectal cancer; IMA = invasive mucinous adenocarcinoma; KRAS WT = Kirsten rat sarcoma viral oncogene homolog wild-type; NSCLC = non-small cell lung cancer; RCC = renal cell carcinoma Note, for pancreatic cancer, where reported (Jonna et al. 2019), all cases were KRAS WT