Thoidingjam Shivani, Sriramulu Sushmitha, Hassan Oudai, Brown Stephen L, Siddiqui Farzan, Movsas Benjamin, Gadgeel Shirish, Nyati Shyam
Department of Radiation Oncology, Henry Ford Health, Detroit, MI 48202, USA.
Department of Surgical Pathology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI 48202, USA.
Cancers (Basel). 2024 Sep 27;16(19):3291. doi: 10.3390/cancers16193291.
: 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. : We hypothesize that BUB1 (Ser/Thr kinase) is overexpressed in lung cancers and its inhibition will sensitize lung cancers to chemoradiation. : 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. : 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. : 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.
尽管靶向治疗和免疫治疗取得了进展，但微管稳定剂（紫杉醇、多西他赛）、DNA嵌入铂类药物（顺铂）等传统治疗方法以及放射治疗对于局部晚期和转移性肺癌的治疗仍然至关重要。识别新的分子靶点可以提高这些治疗方法的疗效。：我们假设BUB1（丝氨酸/苏氨酸激酶）在肺癌中过度表达，抑制它将使肺癌对放化疗敏感。：在细胞增殖和放射增敏试验中，将BUB1抑制剂（BAY1816032）与顺铂、紫杉醇、PARP抑制剂奥拉帕利以及放疗联合使用。生化和分子试验评估了对DNA损伤信号传导和细胞死亡的影响。：肺肿瘤微阵列（TMA）的免疫染色证实，与正常组织相比，非小细胞肺癌（NSCLC）和小细胞肺癌（SCLC）中BUB1表达更高。在NSCLC中，BUB1的过度表达与TP53突变的表达直接相关，并且在NSCLC和SCLC患者中总体生存率较差。BAY1816032使肺癌细胞系对紫杉醇和奥拉帕利产生协同增敏作用，并增强了NSCLC和SCLC中放疗对细胞的杀伤作用。分子分析表明向促凋亡和抗增殖状态转变，这通过BAX、BCL2、PCNA以及半胱天冬酶-9和-3表达的改变得以证明。：BUB1表达升高与肺癌患者较差的生存率相关。抑制BUB1使NSCLC和SCLC对化疗（顺铂、紫杉醇）、靶向治疗（奥拉帕利）和放疗敏感。此外，我们还提出了一个新发现，即抑制BUB1使NSCLC和SCLC对放疗和放化疗敏感。我们的结果表明，抑制BUB1是使肺癌对放疗和放化疗敏感的一种有前景的策略。
