Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.
Cancer. 2018 Sep 15;124(18):3693-3705. doi: 10.1002/cncr.31600. Epub 2018 Oct 5.
Patients with advanced primary and recurrent salivary duct carcinoma (SDC), a rare and lethal malignancy, have limited therapeutic options. Novel small-molecule agents aimed at targeting critical signaling associated with SDC tumorigenesis may lead to new therapeutic options for patients with these tumors. The human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K) axis, an important oncogenic pathway, has been targeted for therapy in several solid tumors. Currently, little is known about the role and clinical implications of alterations of the HER2/PI3K pathway in patients with SDC.
The authors investigated the clinicopathologic features, genetic alterations, and expression of key members of the HER2/PI3K pathway in 43 primary tumors and conducted in vitro functional and targeted drug-response analyses on cell lines derived from salivary epithelial carcinomas.
In primary tumors, loss of phosphatase and tensin homolog (PTEN) expression was identified in 22 of 43 tumors (51%), overexpression of HER2 was observed in 12 of 43 tumors (28%), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations were identified in 12 of 43 tumors (28%). Phosphorylated protein kinase B (p-AKT) was highly expressed in most tumors. Most tumors (70%) displayed mutually exclusive alterations of PI3K members, whereas 8 tumors (19%) had 2 or more concurrent abnormalities. In vitro studies demonstrated a direct association between PTEN loss and PI3K pathway activation and evidence of response to combined PI3Kα and PI3Kβ and/or pan-PI3K inhibitors.
The current analyses reveal frequent PTEN loss and mutually exclusive alterations of key PI3K pathway members in SDC and demonstrate in vitro evidence of a response to pan-PI3K inhibitors. These results provide a framework for a biomarker-based substratification of patients with SDC in future targeted therapy. Cancer 2018;124:3523-32. © 2018 American Cancer Society.
晚期原发性和复发性涎腺癌（SDC）是一种罕见且致命的恶性肿瘤，患者的治疗选择有限。针对与 SDC 肿瘤发生相关的关键信号通路的新型小分子药物可能为这些肿瘤患者带来新的治疗选择。人表皮生长因子受体 2（HER2）/磷酸肌醇 3-激酶（PI3K）轴是一种重要的致癌途径，已在多种实体肿瘤中被靶向用于治疗。目前，HER2/PI3K 通路改变在 SDC 患者中的作用和临床意义知之甚少。
作者研究了 43 例原发性肿瘤的临床病理特征、基因改变以及 HER2/PI3K 通路关键成员的表达，并对来源于涎腺上皮癌的细胞系进行了体外功能和靶向药物反应分析。
在原发性肿瘤中，43 例肿瘤中有 22 例（51%）存在磷酸酶和张力蛋白同源物（PTEN）表达缺失，12 例（28%）存在 HER2 过表达，43 例肿瘤中有 12 例（28%）存在磷脂酰肌醇-4,5-二磷酸 3-激酶催化亚单位α（PIK3CA）突变。大多数肿瘤中磷酸化蛋白激酶 B（p-AKT）高表达。大多数肿瘤（70%）存在 PI3K 成员的相互排斥改变，而 8 例肿瘤（19%）存在 2 种或更多种同时存在的异常。体外研究表明，PTEN 缺失与 PI3K 通路激活之间存在直接关联，并证实对 PI3Kα 和 PI3Kβ 联合以及/或全 PI3K 抑制剂有反应。
目前的分析揭示了 SDC 中经常出现的 PTEN 缺失和关键 PI3K 通路成员的相互排斥改变，并在体外证实了对全 PI3K 抑制剂的反应。这些结果为未来靶向治疗中 SDC 患者的基于生物标志物的分层提供了框架。癌症 2018；124:3523-32。©2018 美国癌症协会。
