Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2021 Jun 1;27(11):3154-3166. doi: 10.1158/1078-0432.CCR-20-3605. Epub 2021 Apr 6.
Oncogenic fusions involving the () gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion-driven cancers.
We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks and .
Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, fusion) and lung (LUAD-0061AS3, fusion) cancer cells harboring fusions or amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with fusion) PDX tumors induced regression of tumors by 50%-100%. Afatinib was much less effective at blocking tumor growth.
Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of fusion-dependent tumorigenesis and in breast, lung, and ovarian patient-derived cancer models.
涉及 () 基因的致癌融合大约存在于 0.2%的多种组织学癌症中。由此产生的嵌合 NRG1 蛋白主要与 HER3 结合，导致 HER3-HER2 二聚化，并激活下游的生长和存活途径。因此，HER3 是 NRG1 融合驱动癌症治疗的合理靶点。
我们开发了新型的 NRG1 重排癌症的患者来源和同源模型，并研究了抗 HER3 抗体 seribantumab 对信号网络生长和激活的影响。
seribantumab 抑制了 MCF-7 细胞中 NRG1 刺激的生长以及携带 融合或 扩增（HCC-95）的患者来源的乳腺癌（MDA-MB-175-VII， 融合）和肺癌（LUAD-0061AS3， 融合）癌细胞的生长。此外，seribantumab 抑制了表达 融合（HBECp53-CD74-NRG1）的 HBEC 细胞的生长，并诱导 MDA-MB-175-VII 和 LUAD-0061AS3 细胞凋亡。在 seribantumab 处理的细胞中观察到促凋亡蛋白的诱导和细胞周期调节剂 cyclin D1 的表达降低。seribantumab 处理 MDA-MB-175-VII、LUAD-0061AS3 和 HBECp53-CD74-NRG1 细胞可降低 EGFR、HER2、HER3、HER4 和已知的下游信号分子如 AKT 和 ERK1/2 的磷酸化。值得注意的是，seribantumab 给药可使携带 LUAD-0061AS3 患者衍生异种移植（PDX）和 OV-10-0050（卵巢癌与 融合）PDX 肿瘤的小鼠肿瘤消退 50%-100%。阿法替尼在阻断肿瘤生长方面的效果要差得多。
seribantumab 治疗阻断了四个 ERBB 家族成员和下游信号的激活，导致抑制了在乳腺癌、肺癌和卵巢患者来源的癌症模型中依赖于 NRG1 融合的肿瘤发生和生长。
