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HER4 and EGFR Activate Cell Signaling in NRG1 Fusion-Driven Cancers: Implications for HER2-HER3-specific Versus
Hibiki Udagawa1, Monique B Nilsson2, Jacqulyne P Robichaux2
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Introduction:
NRG1 gene fusions are clinically actionable alterations identified in NSCLC and other tumors. Previous studies have reported that NRG1 fusions signal through HER2 and HER3 but, thus far, strategies targeting HER3 specifically or HER2-HER3 signaling have exhibited modest activity in patients with NSCLC 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 is not fully understood.
Methods:
We investigated the role of HER4 and EGFR-HER3 signaling in NRG1 fusion-positive cancers using Ba/F3 models engineered to express various HER family members in combination with NRG1 fusions and in vitro and in vivo models of NRG1 fusion-positive cancer.
Results:
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 were more effective than tyrosine kinase inhibitors 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.
Conclusions:
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.
Insights
NRG1 fusions in NSCLC can be targeted by blocking HER4 and EGFR signaling. Pan-HER inhibition, including HER4 and EGFR, shows greater effectiveness than targeting HER3 or HER2-HER3 alone for NRG1 fusion-positive cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- NRG1 gene fusions are actionable alterations in non-small cell lung cancer (NSCLC) and other tumors.
- Previous strategies targeting HER3 or HER2-HER3 signaling in NRG1 fusion-positive NSCLC showed limited efficacy.
- The role of HER4 and other HER family members in NRG1 fusion-driven cancers remains incompletely understood.
Purpose of the Study:
- To investigate the involvement of HER4 and EGFR-HER3 signaling pathways in NRG1 fusion-positive cancers.
- To evaluate the efficacy of targeting these pathways in preclinical models of NRG1 fusion-positive cancer.
Main Methods:
- Utilized Ba/F3 cell models engineered with NRG1 fusions and various HER family members.
- Employed in vitro and in vivo models of NRG1 fusion-positive cancer.
- Assessed the impact of targeted therapies, including EGFR and HER2 inhibitors, and pan-HER inhibitors.
Main Results:
- NRG1 fusions activate downstream signaling and promote tumor cell growth via HER4, independent of other HER family members.
- EGFR-HER3 signaling is also activated, necessitating combined inhibition for effective tumor growth control.
- Combination therapy with anti-EGFR (cetuximab) and anti-HER2 (trastuzumab, pertuzumab) antibodies demonstrated synergistic effects.
- Pan-HER tyrosine kinase inhibitors were superior to more specific inhibitors, though pathway dependence varied by cancer type.
Conclusions:
- Pan-HER inhibition, encompassing HER4 and EGFR blockade, is a more effective therapeutic strategy for NRG1 fusion-positive cancers than selective HER3 or HER2-HER3 targeting.
- Understanding the specific HER family member dependencies is crucial for optimizing treatment in different NRG1 fusion-positive cancers.
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