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付 玮, 宁 静, 付 伟, 张 静, 丁 士. [Effect of CMTM6 on PD-L1 in Helicobacter pylori infected gastric epithelial cells]. BEIJING DA XUE XUE BAO. YI XUE BAN = JOURNAL OF PEKING UNIVERSITY. HEALTH SCIENCES 2025; 57:245-252. [PMID: 40219552 PMCID: PMC11992445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Indexed: 04/14/2025]
Abstract
OBJECTIVE To explore the changes of CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) and programmed death-ligand 1 (PD-L1) expression in gastric mucosal epithelial cells after Helicobacter pylori infection and the regulation of CMTM6 on PD-L1, and to analyze the mRNA expression differences before and after CMTM6 gene knock-out in helicobacter pylori infected gastric epithelial cells by microarray analysis. METHODS The standard Helicobacter pylori strain ATCC 26695 was co-cultured with human gastric epithelial cell GES-1 for 6, 24 and 48 hours, and the mRNA and protein levels of CMTM6 and PD-L1 were detected by real-time quantitative PCR and Western blot. Using CRISPR/Cas9 to construct CMTM6 gene knockout plasmid and knockout CMTM6 gene of GES-1 cells. Helicobacter pylori was co-cultured with CMTM6 gene knockout and wild type GES-1 cells for 48 hours to detect PD-L1 transcription and protein level changes, and CMTM6 gene knockout GES-1 cells were treated with the proteasome inhibitor MG-132 to detect the changes in PD-L1 protein levels. Agilent Human ceRNA Microarray 2019 was used to detect the differentially expressed genes in CMTM6 gene knockout and wild-type GES-1 cells co-cultured with Hp for 48 hours, and the signal pathway of differentially expressed genes enrichment was analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS The mRNA and protein levels of CMTM6 and PD-L1 in GES-1 cells were significantly up-regulated after Helicobacter pylori infection, and CMTM6 mRNA was most significantly up-regulated 48 hours after infection. After CMTM6 gene knockout, the CD274 gene transcription level of Helicobacter pylori infected GES-1 cells did not change significantly, but PD-L1 protein level was significantly down-regulated, and the PD-L1 level increased after the application of proteasome inhibitor MG-132. After CMTM6 gene knockout, 67 genes had more than two times of differential expression. The transcription levels of TMEM68, FERMT3, GPR142, ATP6V1FNB, NOV, UBE2S and other genes were significantly down-regulated. The transcription levels of PCDHGA6, CAMKMT, PDIA2, NTRK3, SPOCK1 and other genes were significantly up-regulated. After CMTM6 gene knockout, ubiquitin-conjugating enzyme E2S (UBE2S) gene expression was significantly down-regulated, which might affect protein ubiquitination degradation. After CMTM6 gene knockout, adrenoceptor alpha 1B (ADRA1B), cholinergic receptor muscarinic 1 (M1), CHRM1, platelet activating factor receptor (PTAFR) gene expression was significantly up-regulated. CONCLUSION Helicobacter pylori infection up-regulates the expression level of CMTM6 in gastric mucosa cells, and CMTM6 can stabilize PD-L1 and maintain the protein level of PD-L1. CMTM6 gene knockout may affect biological behaviors such as protein ubiquitination and cell surface receptor expression.
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Affiliation(s)
- 玮 付
- />北京大学第三医院消化科，幽门螺杆菌感染及上胃肠疾病防治研究北京市重点实验室，北京 100191Department of Gastroenterology, Peking University Third Hospital; Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Beijing 100191, China
| | - 静 宁
- />北京大学第三医院消化科，幽门螺杆菌感染及上胃肠疾病防治研究北京市重点实验室，北京 100191Department of Gastroenterology, Peking University Third Hospital; Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Beijing 100191, China
| | - 伟伟 付
- />北京大学第三医院消化科，幽门螺杆菌感染及上胃肠疾病防治研究北京市重点实验室，北京 100191Department of Gastroenterology, Peking University Third Hospital; Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Beijing 100191, China
| | - 静 张
- />北京大学第三医院消化科，幽门螺杆菌感染及上胃肠疾病防治研究北京市重点实验室，北京 100191Department of Gastroenterology, Peking University Third Hospital; Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Beijing 100191, China
| | - 士刚 丁
- />北京大学第三医院消化科，幽门螺杆菌感染及上胃肠疾病防治研究北京市重点实验室，北京 100191Department of Gastroenterology, Peking University Third Hospital; Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Beijing 100191, China
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Thangaretnam K, Islam MO, Lv J, El-Rifai A, Perloff A, Soutto HL, Peng D, Chen Z. WEE1 inhibition in cancer therapy: Mechanisms, synergies, preclinical insights, and clinical trials. Crit Rev Oncol Hematol 2025; 211:104710. [PMID: 40187712 DOI: 10.1016/j.critrevonc.2025.104710] [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: 03/04/2025] [Accepted: 03/22/2025] [Indexed: 04/07/2025] Open
Abstract
WEE1 is a serine/threonine kinase that regulates the G2/M checkpoint by phosphorylating CDK1, preventing premature mitotic entry and maintaining genomic stability. Many cancers, particularly those with TP53 mutations, upregulate WEE1 to counteract replication stress and DNA damage, making it a key target for therapy. WEE1 inhibitors, especially adavosertib (AZD1775), have shown strong preclinical and clinical activity in ovarian, breast, gastrointestinal, and head and neck cancers. By inducing mitotic catastrophe and increasing DNA damage, WEE1 inhibition enhances the effectiveness of chemotherapies, including platinum-based agents, antimetabolites, and PARP inhibitors. It also synergizes with radiotherapy and immune checkpoint inhibitors, improving responses in tumors with immune evasion. However, challenges such as acquired resistance, toxicity, and patient selection remain obstacles to clinical implementation. Given the expanding role of WEE1 inhibitors in cancer treatment, a comprehensive review is needed to summarize their biological functions, structural regulation, and therapeutic applications. This review highlights key findings from preclinical and clinical studies, explores emerging biomarkers for patient stratification, and discusses strategies to overcome resistance and toxicity. By integrating current knowledge, we aim to provide insights into optimizing WEE1-targeted therapies and guiding future research to maximize their clinical impact in cancer treatment.
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Affiliation(s)
- Krishnapriya Thangaretnam
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Md Obaidul Islam
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Jialun Lv
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | | | - Ava Perloff
- College of Arts and Sciences, University of Miami, FL 33136, USA
| | - Houda L Soutto
- College of Arts and Sciences, University of Miami, FL 33136, USA
| | - Dunfa Peng
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Zheng Chen
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
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Chen A, Yin K, Liu Y, Hu L, Cui Q, Wan X, Yang W. WEE Family Kinase Inhibitors Combined with Sorafenib Can Selectively Inhibit HCC Cell Proliferation. Curr Cancer Drug Targets 2025; 25:370-385. [PMID: 38860904 DOI: 10.2174/0115680096298370240520093003] [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: 01/08/2024] [Revised: 04/10/2024] [Accepted: 04/24/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND Sorafenib is currently the first choice for the treatment of patients with advanced hepatocellular carcinoma, but its therapeutic effect is still limited. OBJECTIVES This study aims to examine whether WEE family kinase inhibitors can enhance the anticancer effect of sorafenib. METHODS We analyzed the expression levels of PKMYT1 kinase and WEE1 kinase in HCC, studied the inhibitory effect of PKMYT1 kinase inhibitor RP-6306, WEE1 kinase inhibitor adavosertib combined with sorafenib on the proliferation of HCC cells, and detected the effect of drug combination on CDK1 phosphorylation. RESULTS We found that PKMYT1 and WEE1 were upregulated in HCC and were detrimental to patient survival. Cell experiments showed that both RP-6306 and adavosertib (1-100 μM) inhibited the proliferation of HCC cell lines in a dose-dependent manner alone, and the combination of the two drugs had a synergistic effect. In HCC cell lines, sorafenib combined with RP-6306 or adavosertib showed a synergistic antiproliferation effect and less toxicity to normal cells. Sorafenib combined with RP-6306 and adavosertib further inhibited the proliferation of HCC cells and caused complete dephosphorylation of CDK1. CONCLUSION Taken together, our findings provide experimental evidence for the future use of sorafenib in combination with RP-6306 or adavosertib for the treatment of HCC.
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Affiliation(s)
- Anling Chen
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Science Island Branch, Graduate School of University of Science and Technology of China, Hefei, 230031, China
| | - Ke Yin
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
| | - Yu Liu
- School of Life Sciences, Bengbu Medical College, Bengbu, 233000, China
| | - Lei Hu
- School of Preclinical Medicine, Wannan Medical College, Wuhu, 241002, China
| | - Qianwen Cui
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Science Island Branch, Graduate School of University of Science and Technology of China, Hefei, 230031, China
| | - Xiaofeng Wan
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
| | - Wulin Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Science Island Branch, Graduate School of University of Science and Technology of China, Hefei, 230031, China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
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Omidvar S, Vahedian V, Sourani Z, Yari D, Asadi M, Jafari N, Khodavirdilou L, Bagherieh M, Shirzad M, Hosseini V. The molecular crosstalk between innate immunity and DNA damage repair/response: Interactions and effects in cancers. Pathol Res Pract 2024; 260:155405. [PMID: 38981346 DOI: 10.1016/j.prp.2024.155405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 06/08/2024] [Accepted: 06/12/2024] [Indexed: 07/11/2024]
Abstract
DNA damage can lead to erroneous alterations and mutations which in turn can result into wide range of disease condition including aging, severe inflammation, and, most importantly, cancer. Due to the constant exposure to high-risk factors such as exogenous and endogenous DNA-damaging agents, cells may experience DNA damage impairing stability and integrity of the genome. These perturbations in DNA structure can arise from several mutations in the genome. Therefore, DNA Damage Repair/Response (DDR) detects and then corrects these potentially tumorigenic problems by inducing processes such as DNA repair, cell cycle arrest, apoptosis, etc. Additionally, DDR can activate signaling pathways related to immune system as a protective mechanism against genome damage. These protective machineries are ignited and spread through a network of molecules including DNA damage sensors, transducers, kinases and downstream effectors. In this review, we are going to discuss the molecular crosstalk between innate immune system and DDR, as well as their potential effects on cancer pathophysiology.
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Affiliation(s)
- Sahar Omidvar
- Cancer Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
| | - Vahid Vahedian
- Department of Hematology, Transfusion Medicine and Cellular Therapy, Division of Hematology/Oncology, Clinical Hospital, Faculty of Medicine, University of Sao Paulo (FMUSP-HC), Sao Paulo, Brazil; Department of Clinical Medicine, Division of Medical Investigation Laboratory (LIM-31), Clinical Hospital, Faculty of Medicine, University of Sao Paulo (FMUSP-HC), Sao Paulo, Brazil; Comprehensive Center for Translational and Precision Oncology (CTO), SP State Cancer Institute (ICESP), Sao Paulo, Brazil.
| | - Zahra Sourani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
| | - Davood Yari
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
| | - Mehrdad Asadi
- Department of Medical Laboratory Sciences and Microbiology, Faculty of Medical Sciences, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran.
| | - Negin Jafari
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Lida Khodavirdilou
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA.
| | - Molood Bagherieh
- Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran.
| | - Moein Shirzad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
| | - Vahid Hosseini
- Department of Medical Laboratory Sciences and Microbiology, Faculty of Medical Sciences, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran; Infectious Diseases Research Center, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran.
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Mecca M, Picerno S, Cortellino S. The Killer's Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer. Int J Mol Sci 2024; 25:2750. [PMID: 38473997 DOI: 10.3390/ijms25052750] [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: 12/20/2023] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
Inflammation is a key contributor to both the initiation and progression of tumors, and it can be triggered by genetic instability within tumors, as well as by lifestyle and dietary factors. The inflammatory response plays a critical role in the genetic and epigenetic reprogramming of tumor cells, as well as in the cells that comprise the tumor microenvironment. Cells in the microenvironment acquire a phenotype that promotes immune evasion, progression, and metastasis. We will review the mechanisms and pathways involved in the interaction between tumors, inflammation, and nutrition, the limitations of current therapies, and discuss potential future therapeutic approaches.
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Affiliation(s)
- Marisabel Mecca
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, PZ, Italy
| | - Simona Picerno
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, PZ, Italy
| | - Salvatore Cortellino
- Laboratory of Preclinical and Translational Research, Responsible Research Hospital, 86100 Campobasso, CB, Italy
- Scuola Superiore Meridionale (SSM), Clinical and Translational Oncology, 80138 Naples, NA, Italy
- S.H.R.O. Italia Foundation ETS, 10060 Candiolo, TO, Italy
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Klapp V, Álvarez-Abril B, Leuzzi G, Kroemer G, Ciccia A, Galluzzi L. The DNA Damage Response and Inflammation in Cancer. Cancer Discov 2023; 13:1521-1545. [PMID: 37026695 DOI: 10.1158/2159-8290.cd-22-1220] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/27/2023] [Accepted: 02/23/2023] [Indexed: 04/08/2023]
Abstract
Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting the demise of cells with unrepairable DNA lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor tumor progression and resistance to therapy. Indeed, DDR signaling in cancer cells has been consistently linked to the inhibition of tumor-targeting immune responses. Here, we discuss the complex interactions between the DDR and inflammation in the context of oncogenesis, tumor progression, and response to therapy. SIGNIFICANCE Accumulating preclinical and clinical evidence indicates that DDR is intimately connected to the emission of immunomodulatory signals by normal and malignant cells, as part of a cell-extrinsic program to preserve organismal homeostasis. DDR-driven inflammation, however, can have diametrically opposed effects on tumor-targeting immunity. Understanding the links between the DDR and inflammation in normal and malignant cells may unlock novel immunotherapeutic paradigms to treat cancer.
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Affiliation(s)
- Vanessa Klapp
- Department of Radiation Oncology, Weill Cornell Medical College, New York, New York
- Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Beatriz Álvarez-Abril
- Department of Radiation Oncology, Weill Cornell Medical College, New York, New York
- Department of Hematology and Oncology, Hospital Universitario Morales Meseguer, Murcia, Spain
| | - Giuseppe Leuzzi
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York
- Herbert Irving Comprehensive Cancer Center, New York, New York
- Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Alberto Ciccia
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York
- Herbert Irving Comprehensive Cancer Center, New York, New York
- Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, New York
- Sandra and Edward Meyer Cancer Center, New York, New York
- Caryl and Israel Englander Institute for Precision Medicine, New York, New York
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Xie D, Jiang B, Wang S, Wang Q, Wu G. The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer. Front Cell Dev Biol 2023; 11:1200466. [PMID: 37305685 PMCID: PMC10248030 DOI: 10.3389/fcell.2023.1200466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/18/2023] [Indexed: 06/13/2023] Open
Abstract
Urologic cancers such as kidney, bladder, prostate, and uroepithelial cancers have recently become a considerable global health burden, and the response to immunotherapy is limited due to immune escape and immune resistance. Therefore, it is crucial to find appropriate and effective combination therapies to improve the sensitivity of patients to immunotherapy. DNA damage repair inhibitors can enhance the immunogenicity of tumor cells by increasing tumor mutational burden and neoantigen expression, activating immune-related signaling pathways, regulating PD-L1 expression, and reversing the immunosuppressive tumor microenvironment to activate the immune system and enhance the efficacy of immunotherapy. Based on promising experimental results from preclinical studies, many clinical trials combining DNA damage repair inhibitors (e.g., PARP inhibitors and ATR inhibitors) with immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) are underway in patients with urologic cancers. Results from several clinical trials have shown that the combination of DNA damage repair inhibitors with immune checkpoint inhibitors can improve objective rates, progression-free survival, and overall survival (OS) in patients with urologic tumors, especially in patients with defective DNA damage repair genes or a high mutational load. In this review, we present the results of preclinical and clinical trials of different DNA damage repair inhibitors in combination with immune checkpoint inhibitors in urologic cancers and summarize the potential mechanism of action of the combination therapy. Finally, we also discuss the challenges of dose toxicity, biomarker selection, drug tolerance, drug interactions in the treatment of urologic tumors with this combination therapy and look into the future direction of this combination therapy.
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Affiliation(s)
| | | | | | - Qifei Wang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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Li Y, Wang X, Hou X, Ma X. Could Inhibiting the DNA Damage Repair Checkpoint Rescue Immune-Checkpoint-Inhibitor-Resistant Endometrial Cancer? J Clin Med 2023; 12:jcm12083014. [PMID: 37109350 PMCID: PMC10144486 DOI: 10.3390/jcm12083014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/23/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Endometrial cancer (EC) is increasingly undermining female health worldwide, with poor survival rates for advanced or recurrent/metastatic diseases. The application of immune checkpoint inhibitors (ICIs) has opened a window of opportunity for patients with first-line therapy failure. However, there is a subset of patients with endometrial cancer who remain insensitive to immunotherapy alone. Therefore, it is necessary to develop new therapeutic agents and further explore reliable combinational strategies to optimize the efficacy of immunotherapy. DNA damage repair (DDR) inhibitors as novel targeted drugs are able to generate genomic toxicity and induce cell death in solid tumors, including EC. Recently, growing evidence has demonstrated the DDR pathway modulates innate and adaptive immunity in tumors. In this review, we concentrate on the exploration of the intrinsic correlation between DDR pathways, especially the ATM-CHK2-P53 pathway and the ATR-CHK1-WEE1 pathway, and oncologic immune response, as well as the feasibility of adding DDR inhibitors to ICIs for the treatment of patients with advanced or recurrent/metastatic EC. We hope that this review will offer some beneficial references to the investigation of immunotherapy and provide a reasonable basis for "double-checkpoint inhibition" in EC.
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Affiliation(s)
- Yinuo Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiangyu Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xin Hou
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiangyi Ma
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Dehghankelishadi P, Badiee P, Maritz MF, Dmochowska N, Thierry B. Bosutinib high density lipoprotein nanoformulation has potent tumour radiosensitisation effects. J Nanobiotechnology 2023; 21:102. [PMID: 36945003 PMCID: PMC10028769 DOI: 10.1186/s12951-023-01848-9] [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: 11/26/2022] [Accepted: 03/07/2023] [Indexed: 03/23/2023] Open
Abstract
Disruption of the cell cycle is among the most effective approach to increase tumour cells' radio-sensitivity. However, the presence of dose-limiting side effects hampers the clinical use of tyrosine kinase inhibitors targeting the cell cycle. Towards addressing this challenge, we identified a bosutinib nanoformulation within high density lipoprotein nanoparticles (HDL NPs) as a promising radiosensitiser. Bosutinib is a kinase inhibitor clinically approved for the treatment of chronic myeloid leukemia that possesses radiosensitising properties through cell cycle checkpoint inhibition. We found that a remarkably high bosutinib loading (> 10%) within HDL NPs could be reliably achieved under optimal preparation conditions. The radiosensitisation activity of the bosutinib-HDL nanoformulation was first assessed in vitro in UM-SCC-1 head and neck squamous cell carcinoma (HNSCC) cells, which confirmed efficient disruption of the radiation induced G2/M cell cycle arrest. Interestingly, the bosutinib nanoformulation out-performed free bosutinib, likely because of the specific affinity of HDL NPs with tumour cells. The combination of bosutinib-HDL NPs and radiotherapy significantly controlled tumour growth in an immunocompetent murine HNSCC model. The bosutinib-HDL nanoformulation also enhanced the radiation induced immune response through the polarisation of tumour associated macrophages towards proinflammatory phenotypes.
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Affiliation(s)
- Pouya Dehghankelishadi
- Future Industries Institute and ARC Centre of Excellence Convergent Bio-Nano Science and Technology, University of South Australia, Mawson Lakes Campus, Adelaide, SA, 5095, Australia
- UniSA Clinical and Health Sciences, University of South Australia, City West Campus, Adelaide, SA, 5000, Australia
| | - Parisa Badiee
- Future Industries Institute and ARC Centre of Excellence Convergent Bio-Nano Science and Technology, University of South Australia, Mawson Lakes Campus, Adelaide, SA, 5095, Australia
- UniSA Clinical and Health Sciences, University of South Australia, City West Campus, Adelaide, SA, 5000, Australia
| | - Michelle F Maritz
- Future Industries Institute and ARC Centre of Excellence Convergent Bio-Nano Science and Technology, University of South Australia, Mawson Lakes Campus, Adelaide, SA, 5095, Australia
| | - Nicole Dmochowska
- Future Industries Institute and ARC Centre of Excellence Convergent Bio-Nano Science and Technology, University of South Australia, Mawson Lakes Campus, Adelaide, SA, 5095, Australia
| | - Benjamin Thierry
- Future Industries Institute and ARC Centre of Excellence Convergent Bio-Nano Science and Technology, University of South Australia, Mawson Lakes Campus, Adelaide, SA, 5095, Australia.
- UniSA Clinical and Health Sciences, University of South Australia, City West Campus, Adelaide, SA, 5000, Australia.
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The Landscape and Therapeutic Targeting of BRCA1, BRCA2 and Other DNA Damage Response Genes in Pancreatic Cancer. Curr Issues Mol Biol 2023; 45:2105-2120. [PMID: 36975505 PMCID: PMC10047276 DOI: 10.3390/cimb45030135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/18/2023] [Accepted: 02/28/2023] [Indexed: 03/08/2023] Open
Abstract
Genes participating in the cellular response to damaged DNA have an important function to protect genetic information from alterations due to extrinsic and intrinsic cellular insults. In cancer cells, alterations in these genes are a source of genetic instability, which is advantageous for cancer progression by providing background for adaptation to adverse environments and attack by the immune system. Mutations in BRCA1 and BRCA2 genes have been known for decades to predispose to familial breast and ovarian cancers, and, more recently, prostate and pancreatic cancers have been added to the constellation of cancers that show increased prevalence in these families. Cancers associated with these genetic syndromes are currently treated with PARP inhibitors based on the exquisite sensitivity of cells lacking BRCA1 or BRCA2 function to inhibition of the PARP enzyme. In contrast, the sensitivity of pancreatic cancers with somatic BRCA1 and BRCA2 mutations and with mutations in other homologous recombination (HR) repair genes to PARP inhibitors is less established and the subject of ongoing investigations. This paper reviews the prevalence of pancreatic cancers with HR gene defects and treatment of pancreatic cancer patients with defects in HR with PARP inhibitors and other drugs in development that target these molecular defects.
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PGD2 displays distinct effects in diffuse large B-cell lymphoma depending on different concentrations. Cell Death Dis 2023; 9:39. [PMID: 36725845 PMCID: PMC9892043 DOI: 10.1038/s41420-023-01311-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 12/27/2022] [Accepted: 01/09/2023] [Indexed: 02/03/2023]
Abstract
Prostaglandin D2 (PGD2), an arachidonic acid metabolite, has been implicated in allergic responses, parasitic infection and tumor development. The biological functions and molecular mechanisms of PGD2 in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we firstly found the high concentration of serum PGD2 and low expression of PGD2 receptor CRTH2 in DLBCL, which were associated with clinical features and prognosis of DLBCL patients. Interestingly, different concentration of PGD2 displayed divergent effects on DLBCL progression. Low-concentration PGD2 promoted cell growth through binding to CRTH2 while high-concentration PGD2 inhibited it via regulating cell proliferation, apoptosis, cell cycle, and invasion. Besides, high-concentration PGD2 could induce ROS-mediated DNA damage and enhance the cytotoxicity of adriamycin, bendamustine and venetoclax. Furthermore, HDAC inhibitors, vorinostat (SAHA) and panobinostat (LBH589) regulated CRTH2 expression and PGD2 production, and CRTH2 inhibitor AZD1981 and high-concentration PGD2 enhanced their anti-tumor effects in DLBCL. Altogether, our findings demonstrated PGD2 and CRTH2 as novel prognostic biomarkers and therapeutic targets in DLBCL, and highlighted the potency of high-concentration PGD2 as a promising therapeutic strategy for DLBCL patients.
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12
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Fan W, Chen X, Li R, Zheng R, Wang Y, Guo Y. A prognostic risk model for ovarian cancer based on gene expression profiles from gene expression omnibus database. Biochem Genet 2023; 61:138-150. [PMID: 35761155 DOI: 10.1007/s10528-022-10232-5] [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: 11/25/2021] [Accepted: 04/18/2022] [Indexed: 01/24/2023]
Abstract
This study explored prognostic genes of ovarian cancer and built a prognostic model based on these genes to predict patient's survival, which is of great significance for improving treatment of ovarian cancer. GSE26712 dataset was downloaded from Gene Expression Omnibus database as training set, while OV-AU dataset was downloaded from ICGC website as validation set. All genes in GSE26712 were analyzed by univariate Cox regression, Lasso regression, and multivariate Cox regression analyses. Then prognosis-related feature genes were screened to construct a multivariate risk model. Meanwhile, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed on samples in the high/low-risk groups using Gene Set Enrichment Analysis (GSEA) software. Finally, survival curve and receiver operating characteristic curve were drawn to verify the validity of the model. Ten feature genes related to prognosis of ovarian cancer were obtained: CMTM6, COLGALT1, F2R, GPR39, IGFBP3, RNF121, MTMR9, ORAI2, SNAI2, ZBTB16. GSEA enrichment analysis showed that there were notable differences in biological pathways such as gap junctions and homologous recombination between the high/low-risk groups. Through further verification of training set and validation set, the 10-gene prognostic model was found to be effective for the prognosis of ovarian cancer patients. In this study, we constructed a 10-gene prognostic model which predicted the prognosis of ovarian cancer patients well by integrating clinical prognostic parameters. It may have certain reference value for subsequent clinical treatment research of ovarian cancer patients and help in clinical treatment decision-making.
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Affiliation(s)
- Wei Fan
- Department of Gynecology, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730030, Gansu Province, China
| | - Xiaoyun Chen
- Department of Gynecology, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730030, Gansu Province, China
| | - Ruiping Li
- Department of Gynecology, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730030, Gansu Province, China
| | - Rongfang Zheng
- Department of Gynecology, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730030, Gansu Province, China
| | - Yunyun Wang
- Lanzhou University Second Hospital, Lanzhou City, 730030, Gansu Province, China
| | - Yuzhen Guo
- Department of Gynecology, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730030, Gansu Province, China.
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13
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Huang X, Liu W, Liu C, Hu J, Wang B, Ren A, Huang X, Yuan Y, Liu J, Li M. CMTM6 as a candidate risk gene for cervical cancer: Comprehensive bioinformatics study. Front Mol Biosci 2022; 9:983410. [PMID: 36589225 PMCID: PMC9798917 DOI: 10.3389/fmolb.2022.983410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022] Open
Abstract
Background: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) is an important programmed cell death 1 ligand 1 regulator (PD-L1). CMTM6 was reported as an important regulator of PD-L1 by promoting PD-L1 expression in tumor cells against T cells. However, the function of CMTM6 in cervical cancer is not well characterized. In addition, the role of CMTM6 in the induction of epithelial-mesenchymal transition (EMT) in the context of cervical cancer is unknown. Methods: In this study, we evaluated the role of CMTM6, including gene expression analysis, miRNA target regulation, and methylation characteristic, using multiple bioinformatics tools based on The Cancer Genome Atlas (TCGA) database. The expression of CMTM6 in cervical cancer tissues and non-cancerous adjacent tissues was assessed using immunohistochemistry. In vitro and in vivo function experiments were performed to explore the effects of CMTM6 on growth and metastasis of cervical cancer. Results: Human cervical cancer tissues showed higher expression of CMTM6 than the adjacent non-cancerous tissues. In vitro assays showed that CMTM6 promoted cervical cancer cell invasion, migration, proliferation, and epithelial-mesenchymal transition via activation of mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK)/p38 signaling pathway. We identified transcription factors (TFs), miRNAs, and immune cells that may interact with CMTM6. Conclusion: These results indicate that CMTM6 is a potential therapeutic target in the context of cervical cancer.
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Affiliation(s)
- Xiaoting Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Wei Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Chunshan Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Jijie Hu
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Baiyao Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Anbang Ren
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Xiaona Huang
- TCM Hospital of Liwan District, Guangzhou, China
| | - Yawei Yuan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Jinquan Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Mingyi Li
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
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14
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Shi C, Qin K, Lin A, Jiang A, Cheng Q, Liu Z, Zhang J, Luo P. The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy. J Exp Clin Cancer Res 2022; 41:268. [PMID: 36071479 PMCID: PMC9450390 DOI: 10.1186/s13046-022-02469-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 08/18/2022] [Indexed: 11/10/2022] Open
Abstract
As our understanding of the mechanisms of cancer treatment has increased, a growing number of studies demonstrate pathways through which DNA damage repair (DDR) affects the immune system. At the same time, the varied response of patients to immune checkpoint blockade (ICB) therapy has prompted the discovery of various predictive biomarkers and the study of combination therapy. Here, our investigation explores the interactions involved in combination therapy, accompanied by a review that summarizes currently identified and promising predictors of response to immune checkpoint inhibitors (ICIs) that are useful for classifying oncology patients. In addition, this work, which discusses immunogenicity and several components of the tumor immune microenvironment, serves to illustrate the mechanism by which higher response rates and improved efficacy of DDR inhibitors (DDRi) in combination with ICIs are achieved.
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15
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Zhang T, Yu H, Dai X, Zhang X. CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment. Front Immunol 2022; 13:971428. [PMID: 35958549 PMCID: PMC9359082 DOI: 10.3389/fimmu.2022.971428] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
The tumor microenvironment (TME) plays crucial roles in regulating tumor occurrence, progress, metastasis and drug resistance. However, it remains largely elusive how the components of TME are regulated to govern its functions in tumor biology. Here, we discussed how the two novel functional proteins, chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) and CMTM4, which involved in the post-translational regulation of PD-L1, modulate the TME functions. The roles of CMTM6 and CMTM4 in regulating TME components, including immune cells and tumor cells themselves were discussed in this review. The potential clinical applications of CMTM6 and CMTM4 as biomarkers to predict therapy efficacy and as new or combined immunotherapy targets are also highlighted. Finally, the current hot topics for the biological function of CMTM6/4 and several significant research directions for CMTM6/4 are also briefly summarized in the review.
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Affiliation(s)
- Tong Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital, Jilin University, Changchun, China
| | - Haixiang Yu
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xiangpeng Dai
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital, Jilin University, Changchun, China
- *Correspondence: Xiangpeng Dai, ; Xiaoling Zhang,
| | - Xiaoling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital, Jilin University, Changchun, China
- *Correspondence: Xiangpeng Dai, ; Xiaoling Zhang,
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16
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Zhang Z, Bu L, Luo J, Guo J. Targeting protein kinases benefits cancer immunotherapy. Biochim Biophys Acta Rev Cancer 2022; 1877:188738. [PMID: 35660645 DOI: 10.1016/j.bbcan.2022.188738] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/16/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023]
Abstract
Small-molecule kinase inhibitors have been well established and successfully developed in the last decades for cancer target therapies. However, intrinsic or acquired drug resistance is becoming the major barrier for their clinical application. With the development of immunotherapies, in particular the discovery of immune checkpoint inhibitors (ICIs), the combination of ICIs with other therapies have recently been extensively explored, among which combination of ICIs with kinase inhibitors achieves promising clinical outcome in a plethora of cancer types. Here we comprehensively summarize the potent roles of protein kinases in modulating immune checkpoints both in tumor and immune cells, and reshaping tumor immune microenvironments by evoking innate immune response and neoantigen generation or presentation. Moreover, the clinical trial and approval of combined administration of kinase inhibitors with ICIs are collected, highlighting the precise strategies to benefit cancer immune therapies.
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Affiliation(s)
- Zhengkun Zhang
- Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Lang Bu
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Junhang Luo
- Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
| | - Jianping Guo
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
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17
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Massey AJ. Chk1 inhibitor-induced DNA damage increases BFL1 and decreases BIM but does not protect human cancer cell lines from Chk1 inhibitor-induced apoptosis. Am J Cancer Res 2022; 12:2293-2309. [PMID: 35693081 PMCID: PMC9185625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/24/2022] [Indexed: 01/09/2023] Open
Abstract
V158411 is a potent, selective Chk1 inhibitor currently in pre-clinical development. We utilised RNA-sequencing to evaluate the gene responses to V158411 treatment. BCL2A1 was highly upregulated in U2OS cells in response to V158411 treatment with BCL2A1 mRNA increased > 400-fold in U2OS but not HT29 cells. Inhibitors of Chk1, Wee1 and topoisomerases but not other DNA damaging agents or inhibitors of ATR, ATM or DNA-PKcs increased BFL1 and decreased BIM protein. Increased BFL1 appeared limited to a subset of approximately 35% of U2OS cells. Out of 24 cell lines studied, U2OS cells were unique in being the only cell line with low basal BFL1 levels to be increased in response to DNA damage. Induction of BFL1 in U2OS cells appeared dependent on PI3K/AKT/mTOR/MEK pathway signalling but independent of NF-κB transcription factors. Inhibitors of MEK, mTOR and PI3K effectively blocked the increase in BFL1 following V15841 treatment. Increased BFL1 expression did not block apoptosis in U2OS cells in response to V158411 treatment and cells with high basal expression of BFL1 readily underwent caspase-dependent apoptosis following Chk1 inhibitor therapy. BFL1 induction in response to Chk1 inhibition appeared to be a rare event that was dependent on MEK/PI3K/AKT/mTOR signalling.
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18
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Gupta N, Huang TT, Horibata S, Lee JM. Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor-resistant cancer. Pharmacol Res 2022; 178:106162. [PMID: 35259479 PMCID: PMC9026671 DOI: 10.1016/j.phrs.2022.106162] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 01/15/2022] [Accepted: 03/03/2022] [Indexed: 02/07/2023]
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have become a mainstay of therapy in ovarian cancer and other malignancies, including BRCA-mutant breast, prostate, and pancreatic cancers. However, a growing number of patients develop resistance to PARPis, highlighting the need to further understand the mechanisms of PARPi resistance and develop effective treatment strategies. Targeting cell cycle checkpoint protein kinases, e.g., ATR, CHK1, and WEE1, which are upregulated in response to replication stress, represents one such therapeutic approach for PARPi-resistant cancers. Mechanistically, activated cell cycle checkpoints promote cell cycle arrest, replication fork stabilization, and DNA repair, demonstrating the interplay of DNA repair proteins with replication stress in the development of PARPi resistance. Inhibitors of these cell cycle checkpoints are under investigation in PARPi-resistant ovarian and other cancers. In this review, we discuss the cell cycle checkpoints and their roles beyond mere cell cycle regulation as part of the arsenal to overcome PARPi-resistant cancers. We also address the current status and recent advancements as well as limitations of cell cycle checkpoint inhibitors in clinical trials.
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Affiliation(s)
- Nitasha Gupta
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tzu-Ting Huang
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sachi Horibata
- Precision Health Program, Michigan State University, East Lansing, MI, USA; Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Jung-Min Lee
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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19
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Yaseen MM, Abuharfeil NM, Darmani H. CMTM6 as a master regulator of PD-L1. Cancer Immunol Immunother 2022; 71:2325-2340. [PMID: 35294592 DOI: 10.1007/s00262-022-03171-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 02/08/2022] [Indexed: 12/15/2022]
Abstract
Immune checkpoint proteins, such as programmed cell death receptor 1 (PD-1) and its ligand (PD-L1), play critical roles in the pathology of chronic inflammatory pathological conditions, particularly cancer. In addition, the activation of PD-1/PD-L1 pathway is involved in mediating resistance to certain anti-cancer chemo- and immuno-therapeutics. Unfortunately, targeting the PD-1/PD-L1 pathway by the available anti-PD-1/PD-L1 drugs can benefit only a small proportion of cancer patients. Thus, studying the factors that regulate the expression of these immune checkpoint proteins is of central importance in this context. Recent investigations have identified CMTM6 and, to a lesser extent, CMTM4, as master regulators of PD-L1 expression in various cancer cells. Understanding the mechanisms by which such proteins upregulate the expression of PD-L1 in tumor cells, and determining the potential regulators of CMTM6 expression in different types of cancers will accelerate the development of new therapeutic targets and/or lead to the enhancement of the currently available PD-1/PD-L1 blockade therapies.
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Affiliation(s)
- Mahmoud Mohammad Yaseen
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid, 22110, Jordan.
| | - Nizar Mohammad Abuharfeil
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid, 22110, Jordan
| | - Homa Darmani
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid, 22110, Jordan
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20
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Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat Rev Drug Discov 2022; 21:440-462. [PMID: 35292771 DOI: 10.1038/s41573-022-00415-5] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2022] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the clinical management of multiple tumours. However, only a few patients respond to ICIs, which has generated considerable interest in the identification of resistance mechanisms. One such mechanism reflects the ability of various oncogenic pathways, as well as stress response pathways required for the survival of transformed cells (a situation commonly referred to as 'non-oncogene addiction'), to support tumour progression not only by providing malignant cells with survival and/or proliferation advantages, but also by establishing immunologically 'cold' tumour microenvironments (TMEs). Thus, both oncogene and non-oncogene addiction stand out as promising targets to robustly inflame the TME and potentially enable superior responses to ICIs.
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21
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The clinical and prognostic significance of CMTM6/PD-L1 in oncology. Clin Transl Oncol 2022; 24:1478-1491. [PMID: 35278198 DOI: 10.1007/s12094-022-02811-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/16/2022] [Indexed: 10/18/2022]
Abstract
The recent discovery of CMTM6 and to a lesser extent CMTM4, two members of the chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family, as master positive regulators of PD-L1 expression, the primary ligand of programmed cell death 1 (PD-1), on tumor and immune cells has opened new horizons for investigating the role of CMTM6/CMTM4 in different aspects of oncology including their clinical and prognostic values in different cancer types. The absence of a specific review article addressing the available results about the clinical and prognostic roles of CMTM6 alone and/or in combination with PD-L1 in cancer has encouraged us to write this paper.
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22
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Wang H, Fan Y, Chen W, Lv Z, Wu S, Xuan Y, Wang C, Lu Y, Guo T, Shen D, Zhang F, Huang Q, Gao Y, Li H, Ma X, Wang B, Huang Y, Zhang X. Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity. Oncoimmunology 2022; 11:2011673. [PMID: 35024247 PMCID: PMC8747516 DOI: 10.1080/2162402x.2021.2011673] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Recent studies have revealed that chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) promotes tumor progression and modulates tumor immunity by regulating programmed death-ligand 1 stability; however, its intrinsic functions and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we show that CMTM6 is upregulated in ccRCC tissues and is strongly associated with advanced tumor grades, early metastases, and a worse prognosis. CMTM6 depletion significantly impaired the proliferation, migration, and invasion of ccRCC cells in vitro and in xenograft mouse models in vivo. In addition, targeting CMTM6 promotes anti-tumor immunity, represented by increased infiltration of CD4+ and CD8+ T cells in syngeneic graft mouse models. Further research revealed that loss of CMTM6 triggered aberrant activation of DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, finally leading to cellular senescence with robust upregulation of numerous chemokines and cytokines. Our findings show for the first time the novel role of CMTM6 in maintaining cancer genome stability and facilitating tumor-mediated immunosuppression, linking DNA damage signaling to the secretion of inflammatory factors. Targeting CMTM6 may improve the treatment of patients with advanced ccRCC.
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Affiliation(s)
- Hanfeng Wang
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Yang Fan
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Weihao Chen
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China.,Medical School of Chinese PLA, Beijing, China
| | - Zheng Lv
- School of Medicine, Nankai University, Tianjin, China
| | - Shengpan Wu
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Yundong Xuan
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China.,Medical School of Chinese PLA, Beijing, China
| | - Chenfeng Wang
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China.,Medical School of Chinese PLA, Beijing, China
| | - Yongliang Lu
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China.,Medical School of Chinese PLA, Beijing, China
| | - Tao Guo
- Medical School of Chinese PLA, Beijing, China.,Senior Department of Paediatrics, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Donglai Shen
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Fan Zhang
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Qingbo Huang
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Yu Gao
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Hongzhao Li
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Xin Ma
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Baojun Wang
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Yan Huang
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Xu Zhang
- Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China
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23
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CMTM6, a potential immunotherapy target. J Cancer Res Clin Oncol 2021; 148:47-56. [PMID: 34783871 DOI: 10.1007/s00432-021-03835-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/18/2021] [Indexed: 10/19/2022]
Abstract
The CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6), which binds to the programmed death ligand 1 (PD-L1) and stabilizes the expression of PD-L1 on the cell surface, has been recently discovered as a novel regulator of PD-L1 expression in cancer. PD-L1 is an immune checkpoint inhibitory molecule that can mediate the immune escape of tumor cells in various tumors and has been studied intensively in recent years. In 2017, two articles simultaneously reported that CMTM6 can stabilize the expression of PD-L1 on the plasma membrane and prevent PD-L1 from being degraded by lysosomes; therefore, CMTM6 may play an important role in tumor cell immune escape and immunosuppression. At present, there are few studies on the relationship between the expression of CMTM6 and PD-L1 in different tumors and diseases. These studies together suggested that CMTM6 may be a potential novel immunotherapy target. In this review, we briefly describe the latest research progresses of CMTM6 in various cancers and other diseases.
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24
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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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WEE1 inhibition reverses trastuzumab resistance in HER2-positive cancers. Gastric Cancer 2021; 24:1003-1020. [PMID: 33723720 DOI: 10.1007/s10120-021-01176-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance. METHODS In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). RESULTS Here, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro. CONCLUSION Taken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients.
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26
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Nam AR, Yoon J, Jin MH, Bang JH, Oh KS, Seo HR, Kim JM, Kim TY, Oh DY. ATR inhibition amplifies antitumor effects of olaparib in biliary tract cancer. Cancer Lett 2021; 516:38-47. [PMID: 34082024 DOI: 10.1016/j.canlet.2021.05.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/17/2021] [Accepted: 05/25/2021] [Indexed: 01/15/2023]
Abstract
Olaparib, a potent PARP inhibitor, has been shown to have great anti-tumor effects in some tumor types. Although biliary tract cancer (BTC) is a good candidate for DNA damage response (DDR)-targeted agents, targeted DDR inhibitors, including olaparib, are currently rarely evaluated in BTC. In our project, a total of ten BTC cell lines were used to assess the efficacy of olaparib. Olaparib alone showed moderate anti-proliferative effects in BTC cells and increased p-ATR and PD-L1 expression levels. In combination with an ATR inhibitor (AZD6738, ceralasertib) showed synergistic anti-proliferative effects and increased DNA strand breaks in vitro. PD-L1 induced by olaparib was also downregulated by ceralasertib through p-STAT-3 and YAP reduction with or without human primary peripheral blood mononuclear cells. In SNU478-xenograft models, the combination treatment significantly suppressed tumor growth. PD-L1 and YAP were strongly downregulated, similar to in vitro conditions, and expression of CXCR2 and CXCR4 was further reduced. In the current ongoing clinical trial (NCT04298021), BTC patients treated with olaparib and ceralasertib combination have shown tumor response. In conclusion, co-targeting of PARP and ATR might be a potential therapeutic approach for patients with BTC.
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Affiliation(s)
- Ah-Rong Nam
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jeesun Yoon
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Mei-Hua Jin
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ju-Hee Bang
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyoung-Seok Oh
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hye-Rim Seo
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea
| | - Jae-Min Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea
| | - Tae-Yong Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Do-Youn Oh
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea.
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27
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Yap TA, Parkes EE, Peng W, Moyers JT, Curran MA, Tawbi HA. Development of Immunotherapy Combination Strategies in Cancer. Cancer Discov 2021; 11:1368-1397. [PMID: 33811048 DOI: 10.1158/2159-8290.cd-20-1209] [Citation(s) in RCA: 203] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 01/03/2021] [Accepted: 02/01/2021] [Indexed: 12/11/2022]
Abstract
Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of the mechanistic underpinnings of the immune system and robust preclinical and clinical drug development strategies. We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials and detailing innovative preclinical model systems being used to develop rational combinations. We also discuss the promise of high-order immunotherapy combinations, as well as novel biomarker and combinatorial trial strategies. SIGNIFICANCE: Although immune-checkpoint inhibitors are approved as dual checkpoint strategies, and in combination with cytotoxic chemotherapy and angiogenesis inhibitors for multiple cancers, patient benefit remains limited. Innovative approaches are required to guide the development of novel immunotherapy combinations, ranging from improvements in preclinical tumor model systems to biomarker-driven trial strategies.
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Affiliation(s)
- Timothy A Yap
- Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eileen E Parkes
- Oxford Institute of Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Weiyi Peng
- Department of Biology and Biochemistry, University of Houston, Houston, Texas
| | - Justin T Moyers
- Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael A Curran
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hussein A Tawbi
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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de Almeida LC, Calil FA, Machado-Neto JA, Costa-Lotufo LV. DNA damaging agents and DNA repair: From carcinogenesis to cancer therapy. Cancer Genet 2021; 252-253:6-24. [DOI: 10.1016/j.cancergen.2020.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 02/09/2023]
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Petroni G, Buqué A, Zitvogel L, Kroemer G, Galluzzi L. Immunomodulation by targeted anticancer agents. Cancer Cell 2021; 39:310-345. [PMID: 33338426 DOI: 10.1016/j.ccell.2020.11.009] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/17/2020] [Accepted: 11/17/2020] [Indexed: 02/08/2023]
Abstract
At odds with conventional chemotherapeutics, targeted anticancer agents are designed to inhibit precise molecular alterations that support oncogenesis or tumor progression. Despite such an elevated degree of molecular specificity, many clinically employed and experimental targeted anticancer agents also mediate immunostimulatory or immunosuppressive effects that (at least in some settings) influence therapeutic efficacy. Here, we discuss the main immunomodulatory effects of targeted anticancer agents and explore potential avenues to harness them in support of superior clinical efficacy.
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Affiliation(s)
- Giulia Petroni
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Aitziber Buqué
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Laurence Zitvogel
- Gustave Roussy Cancer Center, Villejuif, France; INSERM U1015, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France; Faculty of Medicine, Paris-Saclay University, Le Kremlin-Bicêtre, France
| | - Guido Kroemer
- Equipe Labellisée Par La Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA; Université de Paris, Paris, France.
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Chen J, Jia X, Li Z, Song W, Jin C, Zhou M, Xie H, Zheng S, Song P. Targeting WEE1 by adavosertib inhibits the malignant phenotypes of hepatocellular carcinoma. Biochem Pharmacol 2021; 188:114494. [PMID: 33684390 DOI: 10.1016/j.bcp.2021.114494] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/20/2021] [Accepted: 02/24/2021] [Indexed: 10/22/2022]
Abstract
Targeting the cell cycle checkpoints and DNA damage response are promising therapeutic strategies for cancer. Adavosertib is a potent inhibitor of WEE1 kinase, which plays a critical role in regulating cell cycle checkpoints. However, the effect of adavosertib on hepatocellular carcinoma (HCC) treatment, including sorafenib-resistant HCC, has not been thoroughly studied. In this study, we comprehensively investigated the efficacy and pharmacology of adavosertib in HCC therapy. Adavosertib effectively inhibited the proliferation of HCC cells in vitro and suppressed tumor growth in HCC xenografts and patient-derived xenograft (PDX) models in vivo. Additionally, adavosertib treatment effectively inhibited the motility of HCC cells by impairing pseudopodia formation. Further, we revealed that adavosertib induced DNA damage and premature mitosis entrance by disturbing the cell cycle. Thus, HCC cells accumulating DNA damage underwent mitosis without G2/M checkpoint arrest, thereby leading to mitotic catastrophe and apoptosis under adavosertib administration. Given that sorafenib resistance is common in HCC in clinical practice, we also explored the efficacy of adavosertib in sorafenib-resistant HCC. Notably, adavosertib still showed a desirable inhibitory effect on the growth of sorafenib-resistant HCC cells. Adavosertib markedly induced G2/M checkpoint arrest and cell apoptosis in a dose-dependent manner, confirming the similar efficacy of adavosertib in sorafenib-resistant HCC. Collectively, our results highlight the treatment efficacy of adavosertib in HCC regardless of sorafenib resistance, providing insights into exploring novel strategies for HCC therapy.
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Affiliation(s)
- Jian Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Xing Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Zequn Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Wenfeng Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Cheng Jin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Mengqiao Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China.
| | - Penghong Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China.
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Zheng Y, Wang C, Song A, Jiang F, Zhou J, Li G, Zhang W, Ye J, Ding X, Zhang W, Du Y, Zhang H, Wu H, Song X, Wu Y. CMTM6 promotes cell proliferation and invasion in oral squamous cell carcinoma by interacting with NRP1. Am J Cancer Res 2020; 10:1691-1709. [PMID: 32642284 PMCID: PMC7339282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/21/2020] [Indexed: 06/11/2023] Open
Abstract
Previous studies have identified that both CKLF-like MARVEL transmembrane domain-containing member (CMTM6) and Neuropilin-1 (NRP1) played an essential part in regulating tumorigenesis and immune response. However, the potential connection between CMTM6 and NRP1 in oral squamous cell carcinoma (OSCC) remains unknown. In this study, we investigated the clinicopathologic significance of CMTM6 and NRP1 in OSCC. We examined the co-expression of CMTM6 and NRP1 in both OSCC tissues and cell lines. Co-overexpression of CMTM6 and NRP1 was generally highly expressed in cancer tissues and is associated with poor prognosis. Gain- and loss-of-function assays confirmed the oncogenic properties of CMTM6 in OSCC cells. Depletion of NRP1 abrogated tumorigenesis induced by CMTM6. By performing co-immunoprecipitation (co-IP), we discovered a potential interaction between CMTM6 and NRP1. Meanwhile, the stability of CMTM6 was significantly decreased in the NRP1-silencing cells, indicating the involvement of NRP1 in the degradation process of CMTM6. The crosstalk between CMTM6 and NRP1 provided a new insight into the progression of OSCC, which may indicate an alternative strategy for OSCC treatment.
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Affiliation(s)
- Yang Zheng
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - Chundi Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - An Song
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - Feng Jiang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - Junbo Zhou
- Department of Stomatology, Nanjing Integrated Traditional Chinese and Western Medicine HospitalNanjing, China
| | - Gang Li
- Department of Stomatology, Affiliated Hospital of Xuzhou Medical UniversityXuzhou, China
| | - Wei Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
| | - Jinhai Ye
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - Xu Ding
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - Wei Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral Pathology, Affiliated Stomatological Hospital, Nanjing Medical UniversityNanjing, China
| | - Yifei Du
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - Hongchuang Zhang
- Department of Stomatology, Xuzhou No. 1 Peoples HospitalXuzhou, China
- Department of Stomatology, Affiliated Xuzhou Municipal Hospital of Xuzhou Medical UniversityXuzhou, China
| | - Heming Wu
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - Xiaomeng Song
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
| | - Yunong Wu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical UniversityNanjing, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomotology, Nanjing Medical UniversityNanjing, China
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