Background: Despite advances in targeted therapies and immunotherapies, traditional treatments like microtubule stabilizers (paclitaxel, docetaxel), DNA-intercalating platinum drugs (cisplatin), and radiation therapy remain essential for managing locally advanced and metastatic lung cancer. Identifying novel molecular targets could enhance the efficacy of these treatments.Hypothesis: We hypothesize that BUB1 (Ser/Thr kinase) is overexpressed in lung cancers and its inhibition will sensitize lung cancers to chemoradiation.Methods: BUB1 inhibitor (BAY1816032) was combined with cisplatin, paclitaxel, a PARP inhibitor olaparib, and radiation in cell proliferation and radiation-sensitization assays. Biochemical and molecular assays evaluated the impact on DNA damage signaling and cell death.Results: Immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) compared to normal tissues. In NSCLC, BUB1 overexpression correlated directly with the expression of TP53 mutations and poorer overall survival in NSCLC and SCLC patients. BAY1816032 synergistically sensitized lung cancer cell lines to paclitaxel and olaparib and enhanced cell killing by radiation in both NSCLC and SCLC. Molecular analysis indicated a shift towards pro-apoptotic and anti-proliferative states, evidenced by altered BAX, BCL2, PCNA, and Caspases-9 and -3 expressions.Conclusions: Elevated BUB1 expression is associated with poorer survival in lung cancer. Inhibiting BUB1 sensitizes NSCLC and SCLC to chemotherapies (cisplatin, paclitaxel), targeted therapy (olaparib), and radiation. Furthermore, we present the novel finding that BUB1 inhibition sensitized both NSCLC and SCLC to radiotherapy and chemoradiation. Our results demonstrate BUB1 inhibition as a promising strategy to sensitize lung cancers to radiation and chemoradiation therapies.
背景：尽管靶向治疗和免疫疗法取得进展，微管稳定剂（紫杉醇、多西他赛）、DNA嵌入铂类药物（顺铂）及放射治疗等传统疗法仍是局部晚期和转移性肺癌治疗的核心。识别新型分子靶点有望提升这些治疗方案的疗效。 假设：我们推测BUB1（丝氨酸/苏氨酸激酶）在肺癌中过度表达，抑制该蛋白可增强肺癌对放化疗的敏感性。 方法：在细胞增殖与放射增敏实验中，将BUB1抑制剂（BAY1816032）分别与顺铂、紫杉醇、PARP抑制剂奥拉帕利及放射治疗联用。通过生化与分子实验评估其对DNA损伤信号传导和细胞死亡的影响。 结果：肺癌组织芯片免疫染色证实，非小细胞肺癌和小细胞肺癌的BUB1表达均高于正常组织。在非小细胞肺癌中，BUB1过表达与TP53突变呈正相关，且与两类肺癌患者较差的总生存期相关。BAY1816032能协同增强紫杉醇与奥拉帕利对肺癌细胞系的杀伤作用，并提升放射治疗对非小细胞肺癌和小细胞肺癌的细胞灭杀效果。分子分析显示BAX、BCL2、PCNA及Caspase-9/-3表达改变，表明细胞状态向促凋亡和抗增殖方向转变。 结论：BUB1高表达与肺癌患者不良预后相关。抑制BUB1能增强非小细胞肺癌和小细胞肺癌对化疗（顺铂、紫杉醇）、靶向治疗（奥拉帕利）及放射治疗的敏感性。本研究首次发现BUB1抑制可同时提升两类肺癌对放疗及放化疗的敏感性，证明BUB1抑制是增强肺癌放射治疗及放化疗疗效的潜在策略。
BUB1 Inhibition Overcomes Radio- and Chemoradiation Resistance in Lung Cancer
肿瘤(癌症)患者之家