BUB1 inhibition sensitizes lung cancer cell lines to radiotherapy and chemoradiotherapy

Abstract

Background: Lung cancer is a major public health concern, with high incidence and mortality. Despite advances in targeted therapy and immunotherapy, microtubule stabilizers (paclitaxel, docetaxel), DNA intercalating platinum drugs (cisplatin) and radiation therapy continue to play a critical role in the management of locally advanced and metastatic lung cancer. Novel molecular targets would provide opportunities for improving the efficacies of radiotherapy and chemotherapy. Hypothesis: We hypothesize that BUB1 (Ser/Thr kinase) is over-expressed in lung cancers and that its inhibition will sensitize lung cancers to chemoradiation. Methods: BUB1 inhibitor (BAY1816032) was combined with platinum (cisplatin), microtubule poison (paclitaxel), a PARP inhibitor (olaparib) and radiation in cell proliferation and radiation sensitization assays. Biochemical and molecular assays were used to evaluate their impact on DNA damage signaling and cell death mechanisms. Results: BUB1 expression assessed by immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in NSCLC and SCLC compared to that of normal tissues. BUB1 overexpression in lung cancer tissues correlated directly with expression of TP53 mutations in non-small cell lung cancer (NSCLC). Elevated BUB1 levels correlated with poorer overall survival in NSCLC and small cell lung cancer (SCLC) patients. A BUB1 inhibitor (BAY1816032) synergistically sensitized lung cancer cell lines to paclitaxel and olaparib. Additionally, BAY1816032 enhanced cell killing by radiation in both NSCLC and SCLC. Molecular changes following BUB1 inhibition suggest a shift towards pro-apoptotic and anti-proliferative states, indicated by altered expression of BAX, BCL2, PCNA, and Caspases 9 and 3. Conclusion: A direct correlation between BUB1 protein expression and overall survival was shown. BUB1 inhibition sensitized both NSCLC and SCLC to various chemotherapies (cisplatin, paclitaxel) and targeted therapy (PARPi). 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. Key Words: BUB1; Lung cancer; chemotherapy; radiotherapy, chemoradiation, molecular target.

BUB1 Inhibition Sensitizes TNBC Cell Lines to Chemotherapy and Radiotherapy

“…Molecularly targeted agents can enhance chemoradiation sensitivity [ 13 ]. Given BUB1’s strong correlation to aggressiveness and different classes of drugs [ 23 ] and our observation that BUB1 inhibition sensitizes TNBC to radiation and lung cancers to chemoradiation [ 27 , 31 ], we rationalized that combining BUB1 inhibitors would provide strong chemoradiation sensitization in TNBC. Although the effectiveness of the BUB1 inhibitor BAY1816032 was evaluated with PARPi, cisplatin, and paclitaxel in a prior study [ 30 ], the combination with cisplatin resulted in antagonistic effects, and BUB1’s potential role in improving the efficacy of chemoradiation in TNBC was not assessed.…”

“…Therefore, the main objective of this study was to ascertain if BUB1 inhibition improved the effectiveness of chemotherapy and chemoradiation in TNBC cell lines. Given BUB1’s strong correlation to aggressiveness and different classes of drugs [ 23 ], and our observation that BUB1 inhibition sensitizes TNBC to radiation and lung cancers to chemoradiation [ 31 , 32 ], we rationalized that combining BUB1 inhibitors with different classes of drugs (platinum, PARPi, microtubule depolarization inhibitors) would provide strong chemoradiation sensitization in TNBC.…”