Authors' Affiliations: Department of Thoracic/Head and Neck Medical Oncology; Bioinformatics and Computational Biology; Systems Biology, UT MD Anderson Cancer Center, Houston; Hamon Center for Therapeutic Oncology Research and the Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas; and Biomarin Pharmaceuticals Inc., Novato, California.
Clin Cancer Res. 2013 Nov 15;19(22):6322-8. doi: 10.1158/1078-0432.CCR-13-1975. Epub 2013 Sep 27.
Small cell lung carcinoma (SCLC) is an aggressive malignancy affecting nearly 30,000 people annually in the United States. We have previously identified elevated PARP1 levels in SCLC and demonstrated in vitro sensitivity to the PARP inhibitors AZD 2281 and AG014699. Here, we evaluate activity of a novel, potent PARP inhibitor, BMN 673, and identify markers of response as a basis for developing predictive markers for clinical application.
Inhibition of SCLC proliferation by BMN 673 was assayed in vitro and effects on tumor growth were measured in SCLC xenograft models. Protein expression and pathway activation was assessed by reverse phase protein array and western blot analysis. PARP inhibition was confirmed using a PAR ELISA.
We demonstrate striking, single agent activity of BMN 673 in SCLC cell lines and xenografts, with single agent BMN 673 exhibiting in vivo activity similar to cisplatin. Sensitivity to BMN 673 was associated with elevated baseline expression levels of several DNA repair proteins, whereas greater drug resistance was observed in SCLC models with baseline activation of the PI3K/mTOR pathway. Furthermore, we developed and confirmed these data with a novel "DNA repair score" consisting of a group of 17 DNA repair proteins.
Elevated expression of multiple DNA repair proteins, as well as a corresponding "DNA repair protein score," predict response to BMN 673 in in vitro SCLC models. These observations complement recent work in which PI3K inhibition sensitizes breast cancer models to PARP inhibition, suggesting cooperation between DNA repair and PI3K pathways.
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，每年影响美国近 3 万人。我们之前已经确定 SCLC 中 PARP1 水平升高，并证明体外对 PARP 抑制剂 AZD 2281 和 AG014699 敏感。在这里，我们评估了一种新型强效 PARP 抑制剂 BMN 673 的活性，并确定了反应标志物，作为开发用于临床应用的预测标志物的基础。
在体外测定 BMN 673 对 SCLC 增殖的抑制作用，并在 SCLC 异种移植模型中测量对肿瘤生长的影响。通过反相蛋白阵列和 Western blot 分析评估蛋白表达和通路激活。使用 PAR ELISA 确认 PARP 抑制。
我们证明了 BMN 673 在 SCLC 细胞系和异种移植中的惊人的单药活性，单药 BMN 673 表现出与顺铂相似的体内活性。对 BMN 673 的敏感性与几种 DNA 修复蛋白的基线表达水平升高有关，而在基线激活 PI3K/mTOR 通路的 SCLC 模型中观察到更大的耐药性。此外，我们开发并通过一种由 17 种 DNA 修复蛋白组成的新型“DNA 修复评分”证实了这些数据。
多种 DNA 修复蛋白的高表达以及相应的“DNA 修复蛋白评分”可预测体外 SCLC 模型中对 BMN 673 的反应。这些观察结果补充了最近关于 PI3K 抑制使乳腺癌模型对 PARP 抑制敏感的工作，表明 DNA 修复和 PI3K 途径之间存在协同作用。
