预测 ROR1/BCL2 联合靶向治疗肺小细胞癌。
Predicting ROR1/BCL2 combination targeted therapy of small cell carcinoma of the lung.
机构信息
Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, OH, 43210, USA.
The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
出版信息
Cell Death Dis. 2021 Jun 4;12(6):577. doi: 10.1038/s41419-021-03855-w.
Small cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition. Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination. ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C displayed efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in 8 SCLC cell lines. We have shown that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.
小细胞肺癌（SCLC）仍然是一种致命的癌症，5 年生存率不足 10%，因此需要新的治疗方法。受体酪氨酸激酶样孤儿受体 1（ROR1）是一种癌胚蛋白，由于 microRNA 的共同调控，它在多种肿瘤类型中与 BCL2 共同表达，成为治疗靶点。我们假设 ROR1 靶向治疗对小细胞肺癌有效，并与治疗性 BCL2 抑制协同作用。利用组织微阵列（TMA）和福尔马林固定石蜡包埋（FFPE）的 SCLC 患者样本，确定 SCLC 中 ROR1 和 BCL2 表达的流行率。使用 8 种 SCLC 衍生的细胞系来确定小分子 ROR1 抑制剂（KAN0441571C）单独使用以及与 BCL2 抑制剂 venetoclax 联合使用的抗肿瘤活性。利用 Chou-Talalay 方法来确定药物组合的协同作用。在 56 例 SCLC 患者样本中，分别有 93%（52/56）和 86%（48/56）检测到 ROR1 和 BCL2 蛋白表达。同样，通过 qRT-PCR 显示，在 28 例 SCLC 患者样本中，分别有 79%（22/28）和 100%（28/28）检测到 ROR1 和 BCL2 的表达升高。KAN0441571C 在 8 种 SCLC 细胞系中显示出疗效，IC50 为 500 nM 或更低。通过 Chou-Talalay 方法，定义组合指数<1 为协同作用，在 8 种 SCLC 细胞系中显示出 KAN0441571C 与 venetoclax 之间的协同作用。我们已经表明，在 SCLC 模型中，ROR1 抑制与 BCL2 抑制协同作用，并有望成为 SCLC 的新治疗靶点。
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