HER4 and EGFR activate cell signaling in NRG1 fusion-driven cancers: implications for HER2/HER3-specific vs. pan-HER targeting strategies

NRG1 gene fusions are clinically actionable alterations identified in non-small cell lung Cancer (NSCLC) and other tumors. Previous studies have demonstrated that NRG1 fusions signal through HER2/HER3 but thus far strategies targeting HER3 specifically or HER2/HER3 signaling have demonstrated modest activity in NSCLC patients bearing NRG1 fusions. Although NRG1 fusion proteins can bind HER4 in addition to HER3, the contribution of HER4 and other HER family members in NRG1 fusion-positive cancers isn't fully understood. We investigated the role of HER4 as well as EGFR/HER3 signaling in NRG1 fusion-positive cancers using Ba/F3 models engineered to express various HER family members in combination with NRG1 fusions, as well as in vitro and in vivo models of NRG1 fusion-positive Cancer. We determined that NRG1 fusions can stimulate downstream signaling and tumor cell growth through HER4, independent of other HER family members. Moreover, EGFR/HER3 signaling is also activated in cells expressing NRG1 fusions, and inhibition of these receptors is also necessary to effectively inhibit tumor cell growth. We observed that cetuximab, an anti-EGFR antibody, in combination with anti-HER2 Antibodies, trastuzumab and pertuzumab, yielded a synergistic effect. Furthermore, pan-HER tyrosine kinase inhibitors (TKIs) were more effective than TKIs with greater specificity for EGFR, EGFR/HER2 or HER2/HER4, although the relative degree of dependence on EGFR or HER4 signaling varied between different NRG1 fusion-positive cancers. Collectively, our findings indicate that pan-HER inhibition including HER4 and EGFR blockade is more effective than selectively targeting HER3 or HER2/HER3 in NRG1 fusion-positive cancers.

HER family; HER4; NRG1 fusion; Non-small cell lung cancer; Tyrosine kinase inhibitor.