Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancer
Abstract Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhib...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-00947-0 |
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| author | Esther P. B. Rodman Michael J. Emch Xiaonan Hou Archit Bajaj Nicole A. Pearson August J. John Yamillie Ortiz Adam D. Bass Saloni Singh Gustavo Baldassarre Scott H. Kaufmann S. John Weroha John R. Hawse |
| author_facet | Esther P. B. Rodman Michael J. Emch Xiaonan Hou Archit Bajaj Nicole A. Pearson August J. John Yamillie Ortiz Adam D. Bass Saloni Singh Gustavo Baldassarre Scott H. Kaufmann S. John Weroha John R. Hawse |
| author_sort | Esther P. B. Rodman |
| collection | DOAJ |
| description | Abstract Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited the serine/threonine kinases, JNK and ERK, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where the single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer. |
| format | Article |
| id | doaj-art-e44639bf7f4f47ce8e388ad94f066eff |
| institution | Kabale University |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-e44639bf7f4f47ce8e388ad94f066eff2025-08-20T04:01:44ZengNature Portfolionpj Precision Oncology2397-768X2025-07-019111710.1038/s41698-025-00947-0Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancerEsther P. B. Rodman0Michael J. Emch1Xiaonan Hou2Archit Bajaj3Nicole A. Pearson4August J. John5Yamillie Ortiz6Adam D. Bass7Saloni Singh8Gustavo Baldassarre9Scott H. Kaufmann10S. John Weroha11John R. Hawse12Department of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Oncology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Oncology, Mayo ClinicMolecular Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer InstituteDepartment of Oncology, Mayo ClinicDepartment of Oncology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicAbstract Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited the serine/threonine kinases, JNK and ERK, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where the single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer.https://doi.org/10.1038/s41698-025-00947-0 |
| spellingShingle | Esther P. B. Rodman Michael J. Emch Xiaonan Hou Archit Bajaj Nicole A. Pearson August J. John Yamillie Ortiz Adam D. Bass Saloni Singh Gustavo Baldassarre Scott H. Kaufmann S. John Weroha John R. Hawse Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancer npj Precision Oncology |
| title | Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancer |
| title_full | Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancer |
| title_fullStr | Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancer |
| title_full_unstemmed | Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancer |
| title_short | Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancer |
| title_sort | lestaurtinib s antineoplastic activity converges on jak stat signaling to inhibit treatment naive and therapy resistant forms ovarian cancer |
| url | https://doi.org/10.1038/s41698-025-00947-0 |
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