Alvarado Diego, Ligon Gwenda F, Lillquist Jay S, Seibel Scott B, Wallweber Gerald, Neumeister Veronique M, Rimm David L, McMahon Gerald, LaVallee Theresa M
Kolltan Pharmaceuticals., New Haven, Connecticut, United States of America.
Monogram Biosciences, Laboratory Corporation of America® Holdings, South San Francisco, California, United States of America.
PLoS One. 2017 Jul 19;12(7):e0181356. doi: 10.1371/journal.pone.0181356. eCollection 2017.
Head and neck squamous cell carcinoma (HNSCC) accounts for 3-5% of all tumor types and remains an unmet medical need with only two targeted therapies approved to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has been implicated as a disease driver in a number of solid tumors, including a subset of HNSCC. Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 activity. An evaluation of HNSCC patient samples demonstrated that NRG1 expression was significantly associated with expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα). Furthermore, NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFα or contained high levels of EGFR homodimers (H11D) demonstrated a better response to KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC.
头颈部鳞状细胞癌（HNSCC）占所有肿瘤类型的3%-5%，至今仍未得到满足的医疗需求，目前仅有两种靶向疗法获批。表皮生长因子受体（EGFR）/ErbB家族中激酶功能受损的成员ErbB3（HER3），在包括一部分HNSCC在内的多种实体瘤中被认为是疾病驱动因素。在此我们表明，ErbB3激活所需的分子成分，包括其配体神经调节蛋白-1（NRG1），在HNSCC中高度普遍，并且HER2而非EGFR是主要激活ErbB3的激酶伙伴。我们证明西妥昔单抗治疗主要抑制ERK信号通路，而抗ErbB3单克隆抗体KTN3379抑制AKT信号通路，并且双重ErbB受体抑制在HNSCC模型中导致增强的抗肿瘤活性。令人惊讶的是，我们发现虽然NRG1是ErbB3激活所必需的，但它不足以完全预测KTN3379的活性。对HNSCC患者样本的评估表明，NRG1表达与EGFR配体双调蛋白（AREG）和转化生长因子α（TGFα）的表达显著相关。此外，分泌高水平AREG和TGFα或含有高水平EGFR同二聚体（H11D）的NRG1阳性HNSCC细胞系对KTN3379表现出更好的反应。虽然ErbB3和EGFR激活在受体水平上是解偶联的，但它们各自的信号通路通过各自配体的共表达而联系在一起。我们提出，当与HNSCC中的EGFR靶向疗法联合使用时，NRG1表达和EGFR激活特征可能会提高抗ErbB3治疗性单克隆抗体方法的疗效。
