HER4和EGFR在NRG1融合驱动的癌症中激活细胞信号传导:HER2/ HER3特异性vs.pan-HER靶向策略的意义

SCI

18 September 2023

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

（Journal of Thoracic Oncology; IF:20.4）

Udagawa H, Nilsson MB, Robichaux JP, He J, Poteete A, Jiang H, Heeke S, Elamin YY, Shibata Y, Matsumoto S, Yoh K, Okazaki S, Masuko T, Odintsov I, Somwar R, Ladanyi M, Goto K, Heymach JV, HER4 and EGFR activate cell signaling in NRG1 fusion-driven cancers: implications for HER2/HER3-specific vs. pan-HER targeting strategies, Journal of Thoracic Oncology (2023), doi: https://doi.org/10.1016/j.jtho.2023.08.034

Correspondence to：

John V. Heymach

Chair, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD

Anderson Cancer Center

Address; 1515 Holcombe, Houston, TX 77030, USA

Phone: 713-792-6363

FAX: 713-792-1220

E-mail: jheymach@mdanderson.org

Abstract 摘要

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.

NRG1基因融合是在非小细胞肺癌(NSCLC)和其他肿瘤中发现的具有临床指导意义的改变。之前的研究已经证明NRG1融合信号通过HER2/HER3传递，但到目前为止，针对HER3或HER2/HER3信号的特异性靶向策略在携带NRG1融合的NSCLC患者中显示出适度的活性。虽然NRG1融合蛋白除了与HER3结合外，还可以与HER4结合，但HER4和其他HER家族成员在NRG1融合阳性癌症中的作用尚不完全清楚。我们使用Ba/F3模型来研究HER4和EGFR/HER3信号通路在NRG1融合阳性癌症中的作用，该模型被设计成表达各种HER家族成员并结合NRG1融合，以及NRG1融合阳性癌症的体外和体内模型。我们确定NRG1融合可以通过HER4刺激下游信号传导和肿瘤细胞生长，而不依赖于其他HER家族成员。此外，在表达NRG1融合基因的细胞中，EGFR/HER3信号通路也被激活，抑制这些受体也是有效抑制肿瘤细胞生长所必需的。我们观察到抗EGFR抗体cetuximab,与抗HER2抗体trastuzumab 和 pertuzumab联合使用产生了协同作用。此外，pan-HER酪氨酸激酶抑制剂(TKIs)对EGFR、EGFR/HER2或HER2/HER4的特异性高于特异性较高的TKIs，但对EGFR或HER4信号传导的相对依赖程度在不同NRG1融合阳性癌症之间存在差异。总之，我们的研究结果表明，在NRG1融合阳性癌症中，包括HER4和EGFR阻断在内的pan-HER抑制比选择性靶向HER3或HER2/HER3更有效。

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