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Miao Y, Yang S, Zhang F, Li J, Zhang Y. Discovery and biological evaluation of a novel and highly potent JAK2 inhibitor for the treatment of triple negative breast cancer. J Enzyme Inhib Med Chem 2025; 40:2488127. [PMID: 40298145 PMCID: PMC12042240 DOI: 10.1080/14756366.2025.2488127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 03/26/2025] [Accepted: 03/30/2025] [Indexed: 04/30/2025] Open
Abstract
Janus kinase 2 (JAK2) is considered an attractive target for the treatment of triple-negative breast cancer (TNBC). Herein, we discovered six JAK2 inhibitors using structure-based virtual screening and molecular docking. Among them, JNN-5 was the best compound. It indicated strong inhibitory effects on JAK2 in the nanomolar range (IC50 = 0.41 ± 0.03 nM), and high selectivity for JAK2 over JAK1 and JAK3 (selectivity index (SI) > 73.17). Moreover, molecular dynamics (MD) simulation exhibited that JNN-5 bound with high stability to JAK2 JH1. Cellular assays revealed that JNN-5 displayed strong antiproliferative activities in the TNBC cell lines (MDA-MB-468, MDA-MB-213, HCC70, MDA-MB-157). JNN-5 significantly reduced the migration of HUVECs with the dose-dependence. JNN-5 had a significant inhibitory effect on multidrug-resistant MDA-MB-231/ADR (IC50 = 0.37 ± 0.02 μM). These data demonstrate that JNN-5 may be a highly effective and selective antitumor compound for the treatment of TNBC.
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Affiliation(s)
- Yingxiang Miao
- Department of Pharmacy, Affiliated Nantong Hospital 3 of Nantong University, Nantong Third People’s Hospital, Nantong, China
| | - Shudan Yang
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Fang Zhang
- Taizhou School of Clinical Medicine, Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Jindong Li
- Taizhou School of Clinical Medicine, Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Yan Zhang
- Taizhou School of Clinical Medicine, Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
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Zhang LP, Wei YM, Luo MJ, Ren SY, Zhan XW, Wang C, Li ZF, Zhu RM, Yan S, Cheng Y, Xu JL, Yang XJ, Du KL, Wang JQ, Zhang GN, Du DX, Gao R, Zhao DB, Gong JN. Both direct and indirect suppression of MCL1 synergizes with BCLXL inhibition in preclinical models of gastric cancer. Cell Death Dis 2025; 16:170. [PMID: 40075071 PMCID: PMC11904182 DOI: 10.1038/s41419-025-07481-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 02/08/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025]
Abstract
Despite the progress of treatment in gastric cancer (GC), the overall outcomes remain poor in patients with advanced diseases, underscoring the urgency to develop more effective treatment strategies. BH3-mimetic drugs, which inhibit the pro-survival BCL2 family proteins, have demonstrated great therapeutic potential in cancer therapy. Although previous studies have implicated a role of targeting the cell survival pathway in GC, the contribution of different pro-survival BCL2 family proteins in promoting survival and mediating resistance to current standard therapies in GC remains unclear. A systematic study to elucidate the hierarchy of these proteins using clinically more relevant GC models is essential to identify the most effective therapeutic target(s) and rational combination strategies for improving GC therapy. Here, we provide evidence from both in vitro and in vivo studies using a broad panel of GC cell lines, tumoroids, and xenograft models to demonstrate that BCLXL and MCL1, but not other pro-survival BCL2 family proteins, are crucial for GC cells survival. While small molecular inhibitors of BCLXL or MCL1 exhibited some single-agent activity, their combination sufficed to cause maximum killing. However, due to the unsolved cardiotoxicity associated with direct MCL1 inhibitors, finding combinations of agents that indirectly target MCL1 and enable the reduction of doses of BCLXL inhibitors while maintaining their anti-neoplastic effects is potentially a feasible approach for the further development of these compounds. Importantly, inhibiting BCLXL synergized significantly with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induced MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppressed MCL1 transcription via the STAT3/SRF axis. Moreover, co-targeting STAT3 and BCLXL also exhibited synergistic killing, extending beyond HER2-amplified GC. Collectively, our results provide mechanistic rationale and pre-clinical evidence for co-targeting BCLXL and MCL1 (both directly and indirectly) in GC. (i) Gastric cancer cells rely on BCLXL and, to a lesser degree, on MCL1 for survival. The dual inhibition of BCLXL and MCL1 with small molecular inhibitors acts synergistically to kill GC cells, regardless of their TCGA molecular subtypes or the presence of poor prognostic markers. While the effect of S63845 is mediated by both BAX and BAK in most cases, BAX, rather than BAK, acts as the primary mediator of BCLXLi in GC cells. (ii) Inhibiting BCLXL significantly synergizes with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induce MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppress MCL1 transcription via the STAT3/SRF axis. The combination of the STAT3 inhibitor and BCLXL inhibitor also exhibits synergistic killing, extending beyond HER2-amplified GC.
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Affiliation(s)
- Li-Ping Zhang
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yu-Min Wei
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ming-Jie Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China
| | - Shu-Yue Ren
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiang-Wen Zhan
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Chao Wang
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ze-Feng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui-Min Zhu
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shuo Yan
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yu Cheng
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jia-Li Xu
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xing-Jiu Yang
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ke-Lei Du
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China
| | - Jin-Qing Wang
- Department of Gastrointestinal Surgery, The Second Hospital of Shandong University, Jinan, China
| | - Guan-Nan Zhang
- Division of Colorectal Surgery, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - De-Xiao Du
- Department of general surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Ran Gao
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dong-Bing Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jia-Nan Gong
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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3
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Regua AT, Bindal S, Najjar MK, Zhuang C, Khan M, Arrigo ABJ, Gonzalez AO, Zhang XR, Zhu JJ, Watabe K, Lo HW. Dual inhibition of the TrkA and JAK2 pathways using entrectinib and pacritinib suppresses the growth and metastasis of HER2-positive and triple-negative breast cancers. Cancer Lett 2024; 597:217023. [PMID: 38852701 PMCID: PMC11533721 DOI: 10.1016/j.canlet.2024.217023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/26/2024] [Accepted: 06/02/2024] [Indexed: 06/11/2024]
Abstract
HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.
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Affiliation(s)
- Angelina T Regua
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Shivani Bindal
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Mariana K Najjar
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Chuling Zhuang
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Munazza Khan
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Austin B J Arrigo
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Anneliese O Gonzalez
- Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Xinhai R Zhang
- Department of Pathology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jay-Jiguang Zhu
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Hui-Wen Lo
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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Peyvandi S, Bulliard M, Yilmaz A, Kauzlaric A, Marcone R, Haerri L, Coquoz O, Huang YT, Duffey N, Gafner L, Lorusso G, Fournier N, Lan Q, Rüegg C. Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL-6/JAK-induced cancer cell plasticity. J Clin Invest 2024; 134:e166847. [PMID: 38236642 PMCID: PMC10940099 DOI: 10.1172/jci166847] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/17/2024] [Indexed: 03/16/2024] Open
Abstract
Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6-induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.
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Affiliation(s)
- Sanam Peyvandi
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Manon Bulliard
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Alev Yilmaz
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Annamaria Kauzlaric
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Rachel Marcone
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Lisa Haerri
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Oriana Coquoz
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Yu-Ting Huang
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Nathalie Duffey
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Laetitia Gafner
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Girieca Lorusso
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Nadine Fournier
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Qiang Lan
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
- Cell and Tissue Dynamics Research Program, Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Curzio Rüegg
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
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Yunianto I, Currie M, Chitcholtan K, Sykes P. Potential drug repurposing of ruxolitinib to inhibit the JAK/STAT pathway for the treatment of patients with epithelial ovarian cancer. J Obstet Gynaecol Res 2023; 49:2563-2574. [PMID: 37565583 DOI: 10.1111/jog.15761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 07/25/2023] [Indexed: 08/12/2023]
Abstract
AIM This review aimed to describe the potential for therapeutic targeting of the JAK/STAT signaling pathway by repurposing the clinically-approved JAK inhibitor ruxolitinib in the patients with epithelial ovarian cancer (OC) setting. METHODS We reviewed publications that focus on the inhibition of the JAK/STAT pathway in hematological and solid malignancies including OC. RESULTS Preclinical studies showed that ruxolitinib effectively reduces OC cell viability and metastasis and enhances the anti-tumor activity of chemotherapy drugs. There are a number of recent clinical trials exploring the role of JAK/STAT inhibition in solid cancers including OC. Early results have not adequately supported efficacy in solid tumors. However, there are preclinical data and clinical studies supporting the use of ruxolitinib in combination with both chemotherapy and other targeted drugs in OC setting. CONCLUSION Inflammatory conditions and persistent activation of the JAK/STAT pathway are associated with tumourigenesis and chemoresistance, and therapeutic blockade of this pathway shows promising results. For women with OC, clinical investigation exploring the role of ruxolitinib in combination with chemotherapy agents or other targeted therapeutics is warranted.
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Affiliation(s)
- Irfan Yunianto
- Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand
- Department of Biology Education, Universitas Ahmad Dahlan, Indonesia
| | - Margaret Currie
- Department of Pathology and Biomedical Sciences, University of Otago, Christchurch, New Zealand
| | - Kenny Chitcholtan
- Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand
| | - Peter Sykes
- Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand
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Montazeri Aliabadi H, Manda A, Sidgal R, Chung C. Targeting Breast Cancer: The Familiar, the Emerging, and the Uncharted Territories. Biomolecules 2023; 13:1306. [PMID: 37759706 PMCID: PMC10526846 DOI: 10.3390/biom13091306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/16/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
Breast cancer became the most diagnosed cancer in the world in 2020. Chemotherapy is still the leading clinical strategy in breast cancer treatment, followed by hormone therapy (mostly used in hormone receptor-positive types). However, with our ever-expanding knowledge of signaling pathways in cancer biology, new molecular targets are identified for potential novel molecularly targeted drugs in breast cancer treatment. While this has resulted in the approval of a few molecularly targeted drugs by the FDA (including drugs targeting immune checkpoints), a wide array of signaling pathways seem to be still underexplored. Also, while combinatorial treatments have become common practice in clinics, the majority of these approaches seem to combine molecularly targeted drugs with chemotherapeutic agents. In this manuscript, we start by analyzing the list of FDA-approved molecularly targeted drugs for breast cancer to evaluate where molecular targeting stands in breast cancer treatment today. We will then provide an overview of other options currently under clinical trial or being investigated in pre-clinical studies.
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Affiliation(s)
- Hamidreza Montazeri Aliabadi
- Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA
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Abunada A, Sirhan Z, Thyagarajan A, Sahu RP. Tyrosine kinase inhibitors and human epidermal growth factor receptor-2 positive breast cancer. World J Clin Oncol 2023; 14:198-202. [PMID: 37275938 PMCID: PMC10236985 DOI: 10.5306/wjco.v14.i5.198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/28/2023] [Accepted: 04/21/2023] [Indexed: 05/19/2023] Open
Abstract
The body of evidence investigating human epidermal growth factor receptor-2 (HER2) directed therapy in patients with breast cancer (BC) has been growing within the last decade. Recently, the use of tyrosine kinase inhibitors (TKIs) has been of particular interest in the treatment of human malignancies. This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.
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Affiliation(s)
- Aya Abunada
- Department of Pharmacy, Sidra Medicine, Doha 0000, Qatar
| | - Zaid Sirhan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, United States
| | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, United States
| | - Ravi P Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, United States
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Chen Y, Ouyang Y, Li Z, Wang X, Ma J. S100A8 and S100A9 in Cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188891. [PMID: 37001615 DOI: 10.1016/j.bbcan.2023.188891] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 03/31/2023]
Abstract
S100A8 and S100A9 are Ca2+ binding proteins that belong to the S100 family. Primarily expressed in neutrophils and monocytes, S100A8 and S100A9 play critical roles in modulating various inflammatory responses and inflammation-associated diseases. Forming a common heterodimer structure S100A8/A9, S100A8 and S100A9 are widely reported to participate in multiple signaling pathways in tumor cells. Meanwhile, S100A8/A9, S100A8, and S100A9, mainly as promoters, contribute to tumor development, growth and metastasis by interfering with tumor metabolism and the microenvironment. In recent years, the potential of S100A8/A9, S100A9, and S100A8 as tumor diagnostic or prognostic biomarkers has also been demonstrated. In addition, an increasing number of potential therapies targeting S100A8/A9 and related signaling pathways have emerged. In this review, we will first expound on the characteristics of S100A8/A9, S100A9, and S100A8 in-depth, focus on their interactions with tumor cells and microenvironments, and then discuss their clinical applications as biomarkers and therapeutic targets. We also highlight current limitations and look into the future of S100A8/A9 targeted anti-cancer therapy.
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9
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Dai X, Zhu K. Cold atmospheric plasma: Novel opportunities for tumor microenvironment targeting. Cancer Med 2023; 12:7189-7206. [PMID: 36762766 PMCID: PMC10067048 DOI: 10.1002/cam4.5491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/17/2022] [Accepted: 11/17/2022] [Indexed: 02/11/2023] Open
Abstract
With mounting preclinical and clinical evidences on the prominent roles of the tumor microenvironment (TME) played during carcinogenesis, the TME has been recognized and used as an important onco-therapeutic target during the past decade. Delineating our current knowledge on TME components and their functionalities can help us recognize novel onco-therapeutic opportunities and establish treatment modalities towards desirable anti-cancer outcome. By identifying and focusing on primary cellular components in the TME, that is, tumor-infiltrating lymphocytes, tumor-associated macrophages, cancer-associated fibroblasts and mesenchymal stem cells, we decomposed their primary functionalities during carcinogenesis, categorized current therapeutic approaches utilizing traits of these components, and forecasted possible benefits that cold atmospheric plasma, a redox modulating tool with selectivity against cancer cells, may convey by targeting the TME. Our insights may open a novel therapeutic avenue for cancer control taking advantages of redox homeostasis and immunostasis.
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Affiliation(s)
- Xiaofeng Dai
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Kaiyuan Zhu
- Affiliated Hospital of Jiangnan University, Wuxi, China
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10
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Hu Q, Bian Q, Rong D, Wang L, Song J, Huang HS, Zeng J, Mei J, Wang PY. JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens. Front Bioeng Biotechnol 2023; 11:1110765. [PMID: 36911202 PMCID: PMC9995824 DOI: 10.3389/fbioe.2023.1110765] [Citation(s) in RCA: 123] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.
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Affiliation(s)
- Qian Hu
- Department of Pharmacy, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.,Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Qihui Bian
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
| | - Dingchao Rong
- Department of Orthopaedic Surgery, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Leiyun Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Department of Pharmacy, Wuhan First Hospital, Wuhan, China
| | - Jianan Song
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
| | - Hsuan-Shun Huang
- Department of Research, Center for Prevention and Therapy of Gynecological Cancers, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| | - Jun Zeng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Mei
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Peng-Yuan Wang
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
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11
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Makhlin I, McAndrew NP, Wileyto EP, Clark AS, Holmes R, Bottalico LN, Mesaros C, Blair IA, Jeschke GR, Fox KR, Domchek SM, Matro JM, Bradbury AR, Feldman MD, Hexner EO, Bromberg JF, DeMichele A. Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer. NPJ Breast Cancer 2022; 8:122. [PMID: 36369506 PMCID: PMC9652412 DOI: 10.1038/s41523-022-00487-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 10/18/2022] [Indexed: 11/13/2022] Open
Abstract
Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.
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Affiliation(s)
- Igor Makhlin
- Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
| | - Nicholas P McAndrew
- Division of Hematology/Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - E Paul Wileyto
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA
| | - Amy S Clark
- Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Robin Holmes
- University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA
| | - Lisa N Bottalico
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
| | - Clementina Mesaros
- Center for Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
| | - Ian A Blair
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Kevin R Fox
- Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Susan M Domchek
- Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Basser Center at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jennifer M Matro
- Division of Hematology/Oncology, UC San Diego, San Diego, CA, USA
| | - Angela R Bradbury
- Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Michael D Feldman
- Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth O Hexner
- Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | | | - Angela DeMichele
- Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
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12
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Wong GL, Manore SG, Doheny DL, Lo HW. STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges. Semin Cancer Biol 2022; 86:84-106. [PMID: 35995341 PMCID: PMC9714692 DOI: 10.1016/j.semcancer.2022.08.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most commonly diagnosed cancer and second-leading cause of cancer deaths in women. Breast cancer stem cells (BCSCs) promote metastasis and therapeutic resistance contributing to tumor relapse. Through activating genes important for BCSCs, transcription factors contribute to breast cancer metastasis and therapeutic resistance, including the signal transducer and activator of transcription (STAT) family of transcription factors. The STAT family consists of six major isoforms, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6. Canonical STAT signaling is activated by the binding of an extracellular ligand to a cell-surface receptor followed by STAT phosphorylation, leading to STAT nuclear translocation and transactivation of target genes. It is important to note that STAT transcription factors exhibit diverse effects in breast cancer; some are either pro- or anti-tumorigenic while others maintain dual, context-dependent roles. Among the STAT transcription factors, STAT3 is the most widely studied STAT protein in breast cancer for its critical roles in promoting BCSCs, breast cancer cell proliferation, invasion, angiogenesis, metastasis, and immune evasion. Consequently, there have been substantial efforts in developing cancer therapeutics to target breast cancer with dysregulated STAT3 signaling. In this comprehensive review, we will summarize the diverse roles that each STAT family member plays in breast cancer pathobiology, as well as, the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators in the context of breast cancer treatment.
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Affiliation(s)
- Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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13
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Overcoming Resistance to HER2-Directed Therapies in Breast Cancer. Cancers (Basel) 2022; 14:cancers14163996. [PMID: 36010990 PMCID: PMC9406173 DOI: 10.3390/cancers14163996] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary Breast cancer is the most common cancer in women in the United States. Around 15% of all breast cancers overexpress the HER2 protein. These HER2-positive tumors have been associated with aggressive behavior if left untreated. Drugs targeting HER2 have greatly improved the outcomes of patients with HER2-positive tumors in the last decades. Despite these improvements, many patients with early breast cancer have recurrences, and many with advanced disease experience progression of disease on HER2-targeted drugs, suggesting that patients can develop resistance to these medications. In this review, we summarize several mechanisms of resistance to HER2-targeted treatments. Understanding how the tumors grow despite these therapies could allow us to develop better treatment strategies to continue to improve patient outcomes. Abstract Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for around 15% of all breast cancers and was historically associated with a worse prognosis compared with other breast cancer subtypes. With the development of HER2-directed therapies, the outcomes of patients with HER2-positive disease have improved dramatically; however, many patients present with de novo or acquired resistance to these therapies, which leads to early recurrences or progression of advanced disease. In this narrative review, we discuss the mechanisms of resistance to different HER2-targeted therapies, including monoclonal antibodies, small tyrosine kinase inhibitors, and antibody-drug conjugates. We review mechanisms such as impaired binding to HER2, incomplete receptor inhibition, increased signaling from other receptors, cross-talk with estrogen receptors, and PIK3CA pathway activation. We also discuss the role of the tumor immune microenvironment and HER2-heterogeneity, and the unique mechanisms of resistance to novel antibody-drug conjugates. A better understanding of these mechanisms and the potential strategies to overcome them will allow us to continue improving outcomes for patients with breast cancer.
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14
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Shinde A, Kulkoyluoglu Cotul E, Chen H, Smith A, Libring S, Solorio L, Wendt MK. Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer. MOLECULAR BIOMEDICINE 2022; 3:19. [PMID: 35729402 PMCID: PMC9213622 DOI: 10.1186/s43556-022-00079-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/06/2022] [Indexed: 11/10/2022] Open
Abstract
Acquisition of resistance to targeted therapies remains a major clinical obstacle for the HER2+ subtype of breast cancer. Using an isogeneic progression series of HER2+ breast cancer metastasis we demonstrate that metastatic cells have an increased capacity to acquire resistance to the covalent, pan-ErbB inhibitor, neratinib. RNA sequencing analyses comparing parental and metastatic cells identified upregulation of transglutaminase 2 (TG2). Genetic depletion and overexpression approaches established that TG2 is both necessary and sufficient for acquisition of neratinib resistance. Mechanistically, we describe a pathway in which TG2-mediates activation of NF-κB signaling leading to upregulation of IL-6 in metastatic cells. This autocrine expression of IL-6 functions to maintain enhanced levels of TG2 via JAK:STAT3 signaling. This drug persistence feedback loop can be interrupted through the use of the JAK1/2 inhibitor ruxolitinib. In vivo application of ruxolitinib had no effect on tumor growth under non-treated conditions, but effectively prevented acquisition of resistance, leading to tumor regression upon coadministration with neratinib. Overall, our studies reveal a mechanism in metastatic breast cancer cells that predisposes them to acquisition of resistance to ErbB-targeted therapeutics. Clinically, immediate application of ruxolitinib could prevent acquisition of resistance and improve patient responses to HER2-targeted therapies.
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Affiliation(s)
- Aparna Shinde
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA
| | - Eylem Kulkoyluoglu Cotul
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA
| | - Hao Chen
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA
| | - Andrew Smith
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA
| | - Sarah Libring
- Department of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA
| | - Luis Solorio
- Department of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Michael K Wendt
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA.
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15
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Manore SG, Doheny DL, Wong GL, Lo HW. IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment. Front Oncol 2022; 12:866014. [PMID: 35371975 PMCID: PMC8964978 DOI: 10.3389/fonc.2022.866014] [Citation(s) in RCA: 140] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/16/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most commonly diagnosed cancer in women. Metastasis is the primary cause of mortality for breast cancer patients. Multiple mechanisms underlie breast cancer metastatic dissemination, including the interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a pleiotropic cytokine that plays an important role in multiple physiological processes including cell proliferation, immune surveillance, acute inflammation, metabolism, and bone remodeling. IL-6 binds to the IL-6 receptor (IL-6Rα) which subsequently binds to the glycoprotein 130 (gp130) receptor creating a signal transducing hexameric receptor complex. Janus kinases (JAKs) are recruited and activated; activated JAKs, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3) for activation, leading to gene regulation. Constitutively active IL-6/JAK/STAT3 signaling drives cancer cell proliferation and invasiveness while suppressing apoptosis, and STAT3 enhances IL-6 signaling to promote a vicious inflammatory loop. Aberrant expression of IL-6 occurs in multiple cancer types and is associated with poor clinical prognosis and metastasis. In breast cancer, the IL-6 pathway is frequently activated, which can promote breast cancer metastasis while simultaneously suppressing the anti-tumor immune response. Given these important roles in human cancers, multiple components of the IL-6 pathway are promising targets for cancer therapeutics and are currently being evaluated preclinically and clinically for breast cancer. This review covers the current biological understanding of the IL-6 signaling pathway and its impact on breast cancer metastasis, as well as, therapeutic interventions that target components of the IL-6 pathway including: IL-6, IL-6Rα, gp130 receptor, JAKs, and STAT3.
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Affiliation(s)
- Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States.,Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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16
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Effects of Ruxolitinib and Calcitriol Combination Treatment on Various Molecular Subtypes of Breast Cancer. Int J Mol Sci 2022; 23:ijms23052535. [PMID: 35269680 PMCID: PMC8910493 DOI: 10.3390/ijms23052535] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 12/28/2022] Open
Abstract
The anticancer effects of ruxolitinib and calcitriol against breast cancer were reported previously. However, the effect of ruxolitinib and calcitriol combination treatment on various molecular subtypes of breast cancer remains unexplored. In this study, we used MCF-7, SKBR3, and MDA-MB-468 cells to investigate the effect of ruxolitinib and calcitriol combination treatment on cell proliferation, apoptosis, cell cycle, and cell signaling markers, in vitro and in vivo. Our results revealed the synergistic anticancer effect of ruxolitinib and calcitriol combination treatment in SKBR3 and MDA-MB-468 cells, but not in MCF-7 cells in vitro, via cell proliferation inhibition, apoptosis induction, cell cycle arrest, and the alteration of cell signaling protein expression, including cell cycle-related (cyclin D1, CDK1, CDK4, p21, and p27), apoptosis-related (c-caspase and c-PARP), and cell proliferation-related (c-Myc, p-p53, and p-JAK2) proteins. Furthermore, in the MDA-MB-468 xenograft mouse model, we demonstrated the synergistic antitumor effect of ruxolitinib and calcitriol combination treatment, including the alteration of c-PARP, cyclin D1, and c-Myc expression, without significant drug toxicity. The combination exhibited a synergistic effect in HER2-enriched and triple-negative breast cancer subtypes. In conclusion, our results suggest different effects of the combination treatment of ruxolitinib and calcitriol depending on the molecular subtype of breast cancer.
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