Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy
Objectives: The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal target in cancer treatment, driving substantial investigation into PI3K inhibitors (PI3Ki). However, the common on-target adverse effect of hyperglycemia presents a substantial challenge to their clinical application...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000584 |
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| author | Guanqin Jin Shihuang Liu Kewei Zheng Xiaobo Cheng Ranran Chai Wei Ye Wei Wei Yongguo Li Ai Huang Guiling Li Huan Yi Yu Kang |
| author_facet | Guanqin Jin Shihuang Liu Kewei Zheng Xiaobo Cheng Ranran Chai Wei Ye Wei Wei Yongguo Li Ai Huang Guiling Li Huan Yi Yu Kang |
| author_sort | Guanqin Jin |
| collection | DOAJ |
| description | Objectives: The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal target in cancer treatment, driving substantial investigation into PI3K inhibitors (PI3Ki). However, the common on-target adverse effect of hyperglycemia presents a substantial challenge to their clinical application. There is an urgent need to discover an anti-hyperglycemic agent that maintains the efficacy of PI3Ki. Methods: We conducted a comprehensive study to explore the interaction between exogenous hyperinsulinemia and PI3Ki in SKOV3 and OVCAR3 ovarian cancer cell lines. We used Western blotting, CCK-8, and EdU assays to determine the effect of this interaction on cell proliferation. In addition, we evaluated the anti-hyperglycemic effects of dorzagliatin in a PI3Ki-induced hyperglycemic mice model. Cell line-derived xenograft (CDX) models were employed to evaluate the in vivo tumor growth inhibitory effects of combining dorzagliatin with PI3Ki. Results: Western blot analysis demonstrated that insulin activated the AKT/INSR/mTOR pathway, reversing PI3Ki-induced p-AKT inhibition. Insulin also attenuated the anti-proliferative effects of PI3Ki. In the hyperglycemic mouse model, dorzagliatin significantly reduced blood glucose levels compared to controls. The combination therapy group (Dorzagliatin + PI3Ki) in CDX models showed a marked reduction in tumor volume. Dorzagliatin not only mitigated hyperglycemia but also enhanced the anti-tumor effects of PI3Ki. A clinical trial (NCT06117566) in cervical cancer patients supported these findings, showing that dorzagliatin stabilized blood glucose levels, facilitated body weight recovery, and achieved a confirmed partial response (PR). Conclusions: Dorzagliatin shows promise for managing PI3Ki-associated hyperglycemia, thereby enhancing its therapeutic efficacy. The activation of liver glycogen kinase and insulin regulation may be key mechanisms underlying its therapeutic benefits. |
| format | Article |
| id | doaj-art-e3d8486c4b75406eb84a36bfa61e391d |
| institution | OA Journals |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-e3d8486c4b75406eb84a36bfa61e391d2025-08-20T02:28:19ZengElsevierMolecular Metabolism2212-87782025-06-019610215110.1016/j.molmet.2025.102151Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapyGuanqin Jin0Shihuang Liu1Kewei Zheng2Xiaobo Cheng3Ranran Chai4Wei Ye5Wei Wei6Yongguo Li7Ai Huang8Guiling Li9Huan Yi10Yu Kang11Clinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, ChinaDepartment of Gynecologic Oncology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, China; Fujian Province Key Clinical Specialty for Gynecology, Fujian Key Laboratory of Women and Children's Critical Diseases Research, National Key Gynecology Clinical Specialty Construction Institution of China, Fuzhou, 350001, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, ChinaClinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, ChinaClinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, ChinaDepartment of translational medicine, Shanghai Jiatan Pharmatech CO. LTD, Shanghai, 201203, ChinaDepartment of translational medicine, Shanghai Jiatan Pharmatech CO. LTD, Shanghai, 201203, ChinaDepartment of translational medicine, Shanghai Jiatan Pharmatech CO. LTD, Shanghai, 201203, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China; Corresponding author.Department of Gynecologic Oncology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, China; Fujian Province Key Clinical Specialty for Gynecology, Fujian Key Laboratory of Women and Children's Critical Diseases Research, National Key Gynecology Clinical Specialty Construction Institution of China, Fuzhou, 350001, China; Corresponding author.Clinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Corresponding author.Objectives: The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal target in cancer treatment, driving substantial investigation into PI3K inhibitors (PI3Ki). However, the common on-target adverse effect of hyperglycemia presents a substantial challenge to their clinical application. There is an urgent need to discover an anti-hyperglycemic agent that maintains the efficacy of PI3Ki. Methods: We conducted a comprehensive study to explore the interaction between exogenous hyperinsulinemia and PI3Ki in SKOV3 and OVCAR3 ovarian cancer cell lines. We used Western blotting, CCK-8, and EdU assays to determine the effect of this interaction on cell proliferation. In addition, we evaluated the anti-hyperglycemic effects of dorzagliatin in a PI3Ki-induced hyperglycemic mice model. Cell line-derived xenograft (CDX) models were employed to evaluate the in vivo tumor growth inhibitory effects of combining dorzagliatin with PI3Ki. Results: Western blot analysis demonstrated that insulin activated the AKT/INSR/mTOR pathway, reversing PI3Ki-induced p-AKT inhibition. Insulin also attenuated the anti-proliferative effects of PI3Ki. In the hyperglycemic mouse model, dorzagliatin significantly reduced blood glucose levels compared to controls. The combination therapy group (Dorzagliatin + PI3Ki) in CDX models showed a marked reduction in tumor volume. Dorzagliatin not only mitigated hyperglycemia but also enhanced the anti-tumor effects of PI3Ki. A clinical trial (NCT06117566) in cervical cancer patients supported these findings, showing that dorzagliatin stabilized blood glucose levels, facilitated body weight recovery, and achieved a confirmed partial response (PR). Conclusions: Dorzagliatin shows promise for managing PI3Ki-associated hyperglycemia, thereby enhancing its therapeutic efficacy. The activation of liver glycogen kinase and insulin regulation may be key mechanisms underlying its therapeutic benefits.http://www.sciencedirect.com/science/article/pii/S2212877825000584PI3K inhibitor (PI3Ki)HyperglycemiaInsulin signaling pathwayAKT/INSR/mTORDorzagliatinBlood glucose management |
| spellingShingle | Guanqin Jin Shihuang Liu Kewei Zheng Xiaobo Cheng Ranran Chai Wei Ye Wei Wei Yongguo Li Ai Huang Guiling Li Huan Yi Yu Kang Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy Molecular Metabolism PI3K inhibitor (PI3Ki) Hyperglycemia Insulin signaling pathway AKT/INSR/mTOR Dorzagliatin Blood glucose management |
| title | Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy |
| title_full | Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy |
| title_fullStr | Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy |
| title_full_unstemmed | Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy |
| title_short | Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy |
| title_sort | therapeutic management of pi3kα inhibitor induced hyperglycemia with a novel glucokinase activator advancing the frontier of pi3kα inhibitor therapy |
| topic | PI3K inhibitor (PI3Ki) Hyperglycemia Insulin signaling pathway AKT/INSR/mTOR Dorzagliatin Blood glucose management |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000584 |
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