Abstract 4042: Role of individual HER family members and pan-HER targeting treatment strategy in NRG1 fusion positive cancer
Authors: Udagawa Hibiki , Nilsson Monique , He Junqin , Poteete Alissa , Heymach John Victor 
Published: April 2023

Abstract
NRG1 gene fusions are rare, clinically actionable somatic alterations identified in 0.1% of all tumors. 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 can also bind to HER4 in addition to HER3, and the contribution of individual HER family members in tumor cells with NRG1 fusions has not been fully elucidated. To determine the role of individual HER family members in NRG1 fusion positive cancer cells, we engineered Ba/F3 cells to express various HER family members along with NRG1 fusions. Expression of NRG1 fusions in combination with EGFR/HER3, HER2/HER4 or HER4 induced cellular transformation as measured by IL-3 independent growth. These results indicated that in addition to HER2/HER3 signaling, EGFR/HER3, HER4, and to a greater extent, HER2/HER4 signaling, may activate key oncogenic signaling pathways in cells expressing NRG1 fusions. We next assessed whether targeted inhibition of HER family members could inhibit the growth of NRG1 fusion positive cancer cells using our panel of engineered Ba/F3 cells, human tumor cell lines, and xenograft models. Our data indicated that pan-HER tyrosine kinase inhibitors (TKIs), such as poziotinib, were more effective at blocking HER2/HER3, EGFR/HER3 and HER4 signaling in NRG1-fusion expressing cells as compared to TKIs with greater relative specificity for EGFR (erlotinib, lapatinib), HER2 (pyrotinib), EGFR/HER2 (afatinib, dacomitinib, neratinib) or HER2/HER4 (TAS0728,tucatinib). In NRG1 fusion-positive cancer cell lines, poziotinib showed potent anti-tumor cell activity with IC50 values of 0.2 - 0.4 nM. The IC50 values of EGFR/HER2 TKIs were 0.3 - 23 nM, and HER2/HER4 TKIs showed modest activity with IC50 values of 11 - 560 nM. Next, we assessed whether inhibition of HER family dimerization also had activity against tumor cells harboring NRG1 fusions. We observed that pertuzumab, a HER2 antibody which inhibits HER2 dimerization with other HER family members, had improved single agent activity as compared to trastuzumab, a HER2 antibody that inhibits HER2 activation, suggesting crosstalk between HER family members. Moreover, an additive effect was observed when tumor cells were treated with trastuzumab in combination with pertuzumab. Treatment with cetuximab, an antibody that targets EGFR, in combination with trastuzumab and pertuzumab yielded a synergistic effect on tumor cell killing. These data indicate that HER4 and EGFR can play a role in NRG1 fusion-driven signaling through crosstalk with HER2/HER3 and thus, pan-HER/EGFR inhibitors are more effective than EGFR/HER2 or HER2/HER4-selective inhibitors, highlighting the therapeutic potential of targeting multiple members of the HER family in NRG1 fusion driven cancers.
Citation Format: Hibiki Udagawa, Monique Nilsson, Junqin He, Alissa Poteete, John Victor Heymach. Role of individual HER family members and pan-HER targeting treatment strategy in NRG1 fusion positive cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4042.