Abstract 353: Establishment and characterization of neuregulin-1 (NRG1) fusion driven XPDX models
Authors: Simonson Alyssa , Flores Johnnie , Moreno Crystal , Hruzek Justine , Papadopoulos Kyriakos , Rasco Drew , Patnaik Amita , Drengler Ronald , White Allan , Ma Jun , Wick Michael J. 
Published: June 2022

Background: Neuregulin-1 (NRG1) rearrangements drive cancers by binding to ERBB3/ERBB2 heterodimers and activating downstream signaling. NRG1 fusion proteins have recently been identified in several cancer types including lung and ovary. To better understand the role of NRG1 fusions in cancer we established three XenoSTART patient-derived xenograft (XPDX) models driven by NRG1 rearrangements including two CD74-NRG1 lung models designated ST2891 and ST3204 and one SARAF-NRG1 ovary model designated ST2476. These models were established in athymic nude mice and characterized for receptor expression, genomic alterations, and in vivo drug sensitivity.

Methods: ST2891 was established from an excision biopsy collected from a 68-year-old male with NSCLC following treatment with carboplatin/paclitaxel and carboplatin/pemetrexed. ST3204 was established from a lymph node biopsy collected from a 63-year-old female with NSCLC following treatment with cisplatin/pemetrexed. ST2476 was established from primary tissue collected from a chemo naïve 61-year-old female with ovarian cancer. The resulting models were passaged and characterized using immunohistochemical and genomic analysis including WES and RNAseq. In vivo studies were performed testing various chemotherapy and targeted agents; study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Tumor regression (%T/C&lt;0) versus Day 0 tumor volume was also reported.

Results: All models reported ERBB2 and ERBB3 staining in evaluated passages with similar histology compared with archival clinical samples. WES analysis of the three models did not identify any variants in EGFR/ERBB2-4/RAS/RAF genes. RNA sequencing revealed CD74-NRG1 or SARAF-NRG1 gene fusions independently confirmed using molecular studies. In vivo, both lung models were resistant to weekly cisplatin or T-DM1 and daily palbociclib (50 mg/kg) or daily afatinib up to 10 mg/kg. ST3204 was found sensitive to weekly pertuzumab (1 mg/kg). Both lung models were resistant to trastuzumab (1 mg/kg). The ST2476 ovary XPDX was found resistant to endocrine therapies and reported some sensitivity to weekly cisplatin.

Conclusion: We have established and characterized a panel of three XPDX models driven by NRG1 rearrangements including two CD74-NRG1 lung models and one SARAF-NRG1 ovary model. These models are valuable tools for further developing therapies targeting NRG1-driven cancers.

Citation Format: Alyssa Simonson, Johnnie Flores, Crystal Moreno, Justine Hruzek, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Ronald Drengler, Allan White, Jun Ma, Michael J. Wick. Establishment and characterization of neuregulin-1 (NRG1) fusion driven XPDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 353.