Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately impacts Black women and has limited effective therapeutic options. Consequently, there is an urgent need to develop novel approaches for the treatment of TNBC. Previously, we identified monopolar spin...
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Elsevier
2025-08-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000697 |
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| author | Kassidy M. Jungles Caroline R. Bishop Cydnee M. Wilson Meilan Liu Kalli R. Jungles Kari Wilder-Romans Corey W. Speers Lori J. Pierce James M. Rae |
| author_facet | Kassidy M. Jungles Caroline R. Bishop Cydnee M. Wilson Meilan Liu Kalli R. Jungles Kari Wilder-Romans Corey W. Speers Lori J. Pierce James M. Rae |
| author_sort | Kassidy M. Jungles |
| collection | DOAJ |
| description | Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately impacts Black women and has limited effective therapeutic options. Consequently, there is an urgent need to develop novel approaches for the treatment of TNBC. Previously, we identified monopolar spindle kinase I (Mps1 or TTK), which is upregulated in TNBC patients after radiotherapy, as a potential therapeutic target. We found that TTK inhibition sensitizes human TNBC to radiotherapy (RT) both in vitro and in vivo; however, these studies were performed in immunodeficient models. Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. These studies demonstrate that TTK inhibition radiosensitizes syngeneic murine models of TNBC and increases the production of micronuclei and aneuploidy. Mechanistic studies demonstrate that TTK inhibition and RT alter the tumor immune microenvironment of TNBC by modifying the production of antitumoral type I interferon (T1IFN). In vivo, TTK inhibition sensitizes syngeneic models of TNBC to RT. Furthermore, combining TTK inhibition and RT also potentiates T1IFN signaling, suggesting that combination treatment may induce antitumoral immunity in immunocompetent models. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment. |
| format | Article |
| id | doaj-art-827f0aa7cd234a4aaa51d2add9871253 |
| institution | OA Journals |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-827f0aa7cd234a4aaa51d2add98712532025-08-20T02:10:06ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-08-016610119010.1016/j.neo.2025.101190Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signalingKassidy M. Jungles0Caroline R. Bishop1Cydnee M. Wilson2Meilan Liu3Kalli R. Jungles4Kari Wilder-Romans5Corey W. Speers6Lori J. Pierce7James M. Rae8Department of Pharmacology, University of Michigan, Ann Arbor, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United States; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, United StatesDepartment of Pharmacology, University of Michigan, Ann Arbor, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, United States; Department of Internal Medicine, University of Michigan, Ann Arbor, United States; Corresponding author at: 6310 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109.Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately impacts Black women and has limited effective therapeutic options. Consequently, there is an urgent need to develop novel approaches for the treatment of TNBC. Previously, we identified monopolar spindle kinase I (Mps1 or TTK), which is upregulated in TNBC patients after radiotherapy, as a potential therapeutic target. We found that TTK inhibition sensitizes human TNBC to radiotherapy (RT) both in vitro and in vivo; however, these studies were performed in immunodeficient models. Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. These studies demonstrate that TTK inhibition radiosensitizes syngeneic murine models of TNBC and increases the production of micronuclei and aneuploidy. Mechanistic studies demonstrate that TTK inhibition and RT alter the tumor immune microenvironment of TNBC by modifying the production of antitumoral type I interferon (T1IFN). In vivo, TTK inhibition sensitizes syngeneic models of TNBC to RT. Furthermore, combining TTK inhibition and RT also potentiates T1IFN signaling, suggesting that combination treatment may induce antitumoral immunity in immunocompetent models. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment.http://www.sciencedirect.com/science/article/pii/S1476558625000697Monopolar spindle kinase IRadiotherapyRadiosensitizationType I interferonBreast cancer |
| spellingShingle | Kassidy M. Jungles Caroline R. Bishop Cydnee M. Wilson Meilan Liu Kalli R. Jungles Kari Wilder-Romans Corey W. Speers Lori J. Pierce James M. Rae Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling Neoplasia: An International Journal for Oncology Research Monopolar spindle kinase I Radiotherapy Radiosensitization Type I interferon Breast cancer |
| title | Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling |
| title_full | Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling |
| title_fullStr | Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling |
| title_full_unstemmed | Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling |
| title_short | Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling |
| title_sort | targeting monopolar spindle kinase i mps1 or ttk induces radiosensitization in syngeneic models of triple negative breast cancer tnbc and potentiates type i interferon t1ifn signaling |
| topic | Monopolar spindle kinase I Radiotherapy Radiosensitization Type I interferon Breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000697 |
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