TY - JOUR
T1 - HER4 and EGFR Activate Cell Signaling in NRG1 Fusion-Driven Cancers
T2 - Implications for HER2-HER3-specific Versus Pan-HER Targeting Strategies
AU - Udagawa, Hibiki
AU - Nilsson, Monique B.
AU - Robichaux, Jacqulyne P.
AU - He, Junqin
AU - Poteete, Alissa
AU - Jiang, Hong
AU - Heeke, Simon
AU - Elamin, Yasir Y.
AU - Shibata, Yuji
AU - Matsumoto, Shingo
AU - Yoh, Kiyotaka
AU - Okazaki, Shogo
AU - Masuko, Takashi
AU - Odintsov, Igor
AU - Somwar, Romel
AU - Ladanyi, Marc
AU - Goto, Koichi
AU - Heymach, John V.
N1 - Publisher Copyright:
© 2023
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
KW - HER family
KW - HER4
KW - NRG1 fusion
KW - Non–small cell lung cancer
KW - Tyrosine kinase inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85176556845&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2023.08.034
DO - 10.1016/j.jtho.2023.08.034
M3 - Article
C2 - 37678511
AN - SCOPUS:85176556845
SN - 1556-0864
VL - 19
SP - 106
EP - 118
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 1
ER -