Abstract 935: Preclinical activity of seribantumab in gastrointestinal cancers withNRG1fusions

Abstract

Background. Oncogenic rearrangements of the neuregulin 1 gene (NRG1) consist of a 59 partner fused to a 39 NRG1 sequence that retains the EGF-like domain, and are found in 0.2% of solid tumors including lung, breast and gastrointestinal (GI) cancers. Carcinomas of GI origin, including pancreatic and cholangiocarcinoma, represent around 20% of solid tumors harboring NRG1 fusions and there is no approved therapy for this group of cancers. The chimeric NRG1 oncoproteins bind to HER3/ERBB3 leading to trans-activation of other ERBB family members and trigger a signaling cascade that culminates in oncogenesis. Although targeting HER3 represents a rational therapeutic strategy for cancers harboring NRG1 fusions, this has remained relatively unexplored for NRG1 fusion-positive GI malignancies. In this study we investigated the efficacy of the anti-HER3 monoclonal antibody seribantumab in preclinical models of NRG1-driven GI cancers. Methods. We developed models of isogenic pancreatic cancer cells with NRG1 fusions by lentiviral-mediated cDNA expression of ATP1B1-NRG1 and SLC3A2-NRG1 fusions in immortalized pancreatic ductal cells (H6c7). Seribantumab efficacy was evaluated in isogenic cell lines and in patient-derived xenograft (PDX) models of pancreatic adenocarcinoma (CTG-0943, APP-NRG1 fusion) and intrahepatic cholangiocarcinoma (CH-07-0068, RBPMS-NRG1 fusion). Western blotting analysis was used to evaluate protein phosphorylation. Expression of NRG1 fusions was confirmed by RT-PCR and NGS. Results. Expression of NRG1 fusions in H6c7 cells resulted in enhanced phosphorylation of HER3 and AKT and increased sensitivity to afatinib, as compared to empty vector control cells (H6c7-EV). Treatment of H6c7-SLC3A2-NRG1 cells with seribantumab resulted in a dose-dependent inhibition of HER3 and AKT phosphorylation. Seribantumab treatment of H6c7-ATP1B1-NRG1 and H6c7-SLC3A2-NRG1 cells resulted in dose-dependent inhibition of cell growth with IC50 values of 0.05 and 0.2 µM, respectively. In contrast, growth of H6c7-EV cells was much less sensitive to seribantumab (IC50 > 1µM). Tumor growth inhibition was observed after administration of seribantumab to PDX mouse models of pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma. While seribantumab (5 mg and 10 mg per dose, BIW) was equally effective to the clinical equivalent dose of afatinib (5 mg/kg QD) in the cholangiocarcinoma PDX model, the two doses of seribantumab were more effective than afatinib in the pancreatic cancer PDX model, causing tumor shrinkage of up to 55% (23-77% range). There was no shrinkage of afatinib-treated pancreatic PDX tumors. Our results here suggest that seribantumab is effective at reducing tumor growth in preclinical models of gastrointestinal cancers with NRG1 fusions. These data support the use of seribantumab to treat GI and other cancers with NRG1 fusions in the ongoing phase 2 CRESTONE study (NCT#04383210). Citation Format: Igor Odintsov, Allan J. Lui, Paul R. Bloom, Morana Vojnic, Shawn Leland, Marc Ladanyi, Romel Somwar. Preclinical activity of seribantumab in gastrointestinal cancers with NRG1 fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 935.