{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:41:20Z","timestamp":1788176480270,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T00:00:00Z","timestamp":1727395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NCI R21","doi-asserted-by":"publisher","award":["1R21CA252010-01A1"],"award-info":[{"award-number":["1R21CA252010-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HFHS Research Administration Start Up","award":["1R21CA252010-01A1"],"award-info":[{"award-number":["1R21CA252010-01A1"]}]},{"name":"HFHS Proposal Development Award","award":["1R21CA252010-01A1"],"award-info":[{"award-number":["1R21CA252010-01A1"]}]},{"name":"HFHS-Rad Onc Start Up","award":["1R21CA252010-01A1"],"award-info":[{"award-number":["1R21CA252010-01A1"]}]},{"name":"Game on Cancer Award","award":["1R21CA252010-01A1"],"award-info":[{"award-number":["1R21CA252010-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers16193291","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T03:44:13Z","timestamp":1727408653000},"page":"3291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["BUB1 Inhibition Overcomes Radio- and Chemoradiation Resistance in Lung Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Shivani","family":"Thoidingjam","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Henry Ford Health, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushmitha","family":"Sriramulu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Henry Ford Health, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oudai","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Henry Ford Health, Detroit, MI 48202, USA"},{"name":"Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, USA"},{"name":"Department of Radiology, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farzan","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Henry Ford Health, Detroit, MI 48202, USA"},{"name":"Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, USA"},{"name":"Department of Radiology, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Movsas","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Henry Ford Health, Detroit, MI 48202, USA"},{"name":"Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, USA"},{"name":"Department of Radiology, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5240-3811","authenticated-orcid":false,"given":"Shirish","family":"Gadgeel","sequence":"additional","affiliation":[{"name":"Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, USA"},{"name":"Division of Hematology\/Oncology, Department of Medicine, Henry Ford Health, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1435-303X","authenticated-orcid":false,"given":"Shyam","family":"Nyati","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Henry Ford Health, Detroit, MI 48202, USA"},{"name":"Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, USA"},{"name":"Department of Radiology, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. 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