Abstract 1182: Molecular landscape and ErbB family signaling in NRG fusion NSCLC: Therapeutic implications for pan-ErbB family inhibitors
Authors: Udagawa Hibiki , Robichaux Jacqulyne P. , Elamin Yasir Y. , He Junqin , Nilsson Monique B. , Heymach John V. 
Published: June 2022

NRG1 gene fusions are rare clinically actionable somatic alterations identified in 0.1% - 0.2% of all tumors. Currently, there are no approved targeted therapies for patients with NRG1 fusion-positive cancer. Previous studies have demonstrated that NRG1 fusions signal through ErbB/HER family members and that HER2 inhibition has anti-tumor activity in NRG1 fusion driven cancers. However, NRG1 binds HER4 in addition to HER3, and the role of individual HER proteins and NRG1 fusion partners have not been fully elucidated. We hypothesized that HER2 and HER4 signaling may have important roles in NRG1 fusion driven cancers, and pan-HER targeting therapies may be more effective for NRG1 fusion positive cancers than HER2-specific inhibitors alone. To test this hypothesis, we investigated the frequency of the NRG1 fusions across cBioPortal and AACR project GENIE datasets and MD Anderson’s GEMINI databases and found that the incidence of NRG1 fusions in all tumor types was 0.1%. NRG1 fusions were observed in 3.3% of patients with cervical cancers and in 1.8% of breast cancers and 1.3% of non-small cell lung cancers. The most common fusion partner was CD74 (9%) and the second most common fusion partner was SLC3A2 (4%). To determine the role of ErbB signaling in NRG1-fusion positive cancers, we engineered Ba/F3 cells to express various ErbB/HER family members and the most common NRG1 fusion partners. Then, we evaluated different strategies of targeting NRG1-fusion positive cell lines using drugs that predominantly target EGFR, HER2, EGFR/HER2, dimerization, or drugs that are pan-HER inhibitors. In Ba/F3 cells, poziotinib, a pan-HER TKI, showed potent activity against cells harboring NRG1 fusions, with IC50 values of 0.19 - 0.36 nM and relative IC50 values (IC50 value of NRG1 fusion/IC50 value of WT EGFR) of 0.04 – 0.07. TKIs targeting predominately EGFR/HER2 (afatinib, dacomitinib and neratinib) we observed modest activity with IC50 values of 6.8 – 42 nM and relative IC50 values of 0.11 – 0.68. The IC50 values of HER2-specific TKIs (58 – 122 nM) were higher than EGFR/HER2 targeting TKIs, but the relative IC50 values (0.005 – 0.015) were lower than poziotinib. Among antibodies, targeting HER2 dimerization with pertuzumab had better single agent activity (IC50 values of 95 – 156 μg/ml) than trastuzumab which had no in vitro activity. Lastly, an additive effect was seen when trastuzumab was used in combination with pertuzumab, with IC50 values of 0.79 – 1.0 μg/ml, and poziotinib with trastuzumab and pertuzumab further potentiated activity. Taken together, these data suggest that pan-HER inhibition with agents such as poziotinib alone and in combination with inhibition of dimerization appears more effective than selective EGFR/HER2 inhibition and highlights the potential of combining agents with multiple mechanisms of HER family targeting. This pan-HER strategy merits further investigation in the clinic.

Citation Format: Hibiki Udagawa, Jacqulyne P. Robichaux, Yasir Y. Elamin, Junqin He, Monique B. Nilsson, John V. Heymach. Molecular landscape and ErbB family signaling in NRG fusion NSCLC: Therapeutic implications for pan-ErbB family inhibitors [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 1182.