Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
Departments of Pharmacology and Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
Clin Cancer Res. 2018 Dec 15;24(24):6136-6141. doi: 10.1158/1078-0432.CCR-18-1635. Epub 2018 Aug 13.
Lung cancer is the leading cause of cancer-related deaths among men and women. γ-Secretase inhibitors, a class of small-molecule compounds that target the Notch pathway, have been tested to treat non-small-cell lung cancer (NSCLC) in preclinical and clinical trials. Although γ-secretase inhibitors elicit a response in some tumors as single agents and sensitize NSCLC to cytotoxic and targeted therapies, they have not yet been approved for NSCLC therapy. We discuss our recently published preclinical study using the γ-secretase inhibitor AL101, formerly BMS906024, on cell lines and PDX models of NSCLC, primarily lung adenocarcinoma. We propose that Notch pathway mutations may not be the most suitable biomarker for predicting NSCLC response to γ-secretase inhibitors. γ-Secretases have over 100 known γ-secretase cleavage substrates. Many of the γ-secretase substrates are directly involved in carcinogenesis or tumor progression, and are ideal candidates to be the "on-target" biomarkers for γ-secretase inhibitors. We propose the need to systematically test the γ-secretase and other targets as potential biomarkers for sensitivity before continuing clinical trials. Now that we have entered the postgenome/transcriptome era, this goal is easily attainable. Discovery of the biomarker(s) that predict sensitivity to γ-secretase inhibitors would guide selection of the responder population that is most likely to benefit and move the compounds closer to approval for therapeutic use in NSCLC.
肺癌是男性和女性癌症相关死亡的主要原因。γ-分泌酶抑制剂是一类靶向 Notch 通路的小分子化合物，已在临床前和临床试验中进行了治疗非小细胞肺癌（NSCLC）的测试。虽然 γ-分泌酶抑制剂作为单一药物在一些肿瘤中引起反应，并使 NSCLC 对细胞毒性和靶向治疗敏感，但它们尚未被批准用于 NSCLC 治疗。我们讨论了我们最近发表的一项使用 γ-分泌酶抑制剂 AL101（以前称为 BMS906024）在 NSCLC，主要是肺腺癌的细胞系和 PDX 模型中的临床前研究。我们提出 Notch 通路突变可能不是预测 NSCLC 对 γ-分泌酶抑制剂反应的最合适生物标志物。γ-分泌酶具有 100 多种已知的 γ-分泌酶切割底物。许多 γ-分泌酶底物直接参与致癌或肿瘤进展，是作为 γ-分泌酶抑制剂的“靶标”生物标志物的理想候选物。我们提出需要在继续临床试验之前，系统地测试 γ-分泌酶和其他靶点作为潜在的敏感性生物标志物。既然我们已经进入了基因组/转录组后时代，这一目标很容易实现。发现预测对 γ-分泌酶抑制剂敏感性的生物标志物将指导选择最有可能受益的应答人群，并使这些化合物更接近 NSCLC 治疗用途的批准。
