1
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Fife M, Tong M, Das B, Rodriguez R, Chokkalingam P, Carlson RI, de la Monte SM. Chondrosarcoma: Multi-Targeting Therapeutic Effects of Doxorubicin, BEZ235, and the Small Molecule Aspartyl-Asparaginyl-β-hydroxylase Inhibitor SMI1182. Cancers (Basel) 2025; 17:1671. [PMID: 40427168 DOI: 10.3390/cancers17101671] [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: 04/13/2025] [Revised: 05/02/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Chondrosarcoma (CS), the most common malignant bone tumor in adults, exhibits a poor prognosis due to high rates of post-surgical recurrence and metastasis, and resistance to chemotherapy. CS's abundant expression of aspartyl-asparaginyl-β-hydroxylase (ASPH), which drives invasive tumor growth via Notch and PI3K/mTOR activation, opens opportunities for treatment in combination with standard Doxorubicin (DOX) chemotherapy. We hypothesized that the small molecule inhibitor SMI1182, which targets the catalytic domain of ASPH, and BEZ235, which targets PI3K/mTOR, could enhance the chemotherapeutic effects of DOX. Human CS1 (Grade 3) and CDS11 (Grade 2) conventional CS cell lines were treated with broad dose ranges of DOX, BEZ235, or SMI1182 as mono- or combination therapy to assess their anti-tumor effects on cell viability, toxicity, and motility. METHODS Mechanistic studies included the analysis of ASPH expression, Notch signaling, and insulin/IGF/IRS pathway activation through mTOR. DOX, BEZ235, or SMI1182 treatments caused dose-dependent cell loss and cytotoxicity. RESULTS SMI1182 and BEZ235, with or without DOX, significantly reduced directional motility. Combined treatments had additive cytotoxic effects linked to the reduced expression of ASPH, Notch transcription factors, and insulin receptor substrate type I, which positively regulates both ASPH and Notch. CONCLUSIONS Triple-drug treatment with DOX, SMI1182, and BEZ235 could potentially improve disease-free survival with CS by the simultaneous targeting of multiple upstream mediators of aggressive malignant tumor cell behavior.
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Affiliation(s)
- Megan Fife
- Molecular Pharmacology, Physiology, and Biotechnology Graduate Program, Brown University, Providence, RI 02912, USA
| | - Ming Tong
- Department of Medicine, Rhode Island Hospital, Brown University Health, Providence, RI 02912, USA
| | - Bhaskar Das
- Department of Drug and Biotherapeutic Discovery, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York (SUNY), Buffalo, NY 14201, USA
| | - Rene Rodriguez
- Health Research Institute of Asturias (ISPA), University Institute of Oncology of Asturias (IUOPA), 33001 Oviedo, Spain
- CIBER Enoncologia (CIBERONC), 28054 Madrid, Spain
| | - Parthiban Chokkalingam
- Department of Drug and Biotherapeutic Discovery, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York (SUNY), Buffalo, NY 14201, USA
| | - Rolf I Carlson
- Department of Medicine, Rhode Island Hospital, Brown University Health, Providence, RI 02912, USA
| | - Suzanne M de la Monte
- Departments of Pathology and Laboratory Medicine, Neurology, and Neurosurgery, Rhode Island Hospital, Women & Infants Hospital, Brown University Health, Alpert Medical School of Brown University, Providence, RI 02912, USA
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2
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Zhang M, Tan Q, Gonca S, Lan M, Qian BZ, Chen X, Radacsi N. Carrier-Free Cisplatin-Dactolisib Nanoparticles for Enhanced Synergistic Antitumor Efficacy. ACS Biomater Sci Eng 2025; 11:1456-1471. [PMID: 39992316 PMCID: PMC11897951 DOI: 10.1021/acsbiomaterials.4c00672] [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: 04/08/2024] [Revised: 02/04/2025] [Accepted: 02/07/2025] [Indexed: 02/25/2025]
Abstract
Cisplatin (CDDP) is one of the most commonly used chemotherapeutic agents for solid tumors and hematologic malignancy. However, its therapeutic outcomes have remained unsatisfactory due to severe side effects, a short elimination half-life, the emergence of drug resistance, and the induction of metastasis. Combination with other chemotherapeutic agents has been proposed as one strategy to address the drawbacks of CDDP-based therapy. Therefore, this study aimed to boost the antitumor efficacy of cisplatin (CDDP) with a PI3K/mTOR dual inhibitor, dactolisib (BEZ), via a carrier-free codelivery system based on the self-assembly of the coordinated CDDP-BEZ. The synthesized CDDP-BEZ nanoparticles (NPs) possess sensitive pH-responsiveness, facilitating the delivery of both drugs to cancer cells. CDDP-BEZ NPs specifically enhanced cytotoxicity in cancer cells due to the synergy between cisplatin and dactolisib, resulting in augmented DNA damage, activation of mitochondria-dependent apoptosis, and increased inhibition on the PI3K/mTOR signaling axis. The inhibition of tumor migration and metastasis by CDDP-BEZ NPs was observed both in vitro and in vivo. Our data suggest that CDDP-BEZ NPs could serve as a safe and effective platform to maximize the synergy between both drugs in combating cancer, presenting a strategy to promote the therapeutic efficacy of platinum-based chemotherapeutic agents by combining them with PI3K inhibitors.
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Affiliation(s)
- Mei Zhang
- School
of Engineering, Institute for Materials and Processes, University of Edinburgh, Robert Stevenson Road, Edinburgh EH9 3FB, U.K.
- School
of Engineering, Institute for Bioengineering, University of Edinburgh, The King’s Buildings, Edinburgh EH9 3JL, U.K.
| | - Qiuxia Tan
- Key
Laboratory of Hunan Province for Water Environment and Agriculture
Product Safety, College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China
| | - Sevil Gonca
- School
of Engineering, Institute for Bioengineering, University of Edinburgh, The King’s Buildings, Edinburgh EH9 3JL, U.K.
| | - Minhuan Lan
- Key
Laboratory of Hunan Province for Water Environment and Agriculture
Product Safety, College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China
| | - Bin-Zhi Qian
- Medical
Research Council Centre for Reproductive Health, College of Medicine
and Veterinary Medicine, Queen’s
Medical Research Institute University of Edinburgh, Little France Crescent, Edinburgh EH16 4TJ, U.K.
- Fudan
University Shanghai Cancer Center, Department of Oncology, Shanghai
Medical College, The Human Phenome Institute, Zhangjiang-Fudan International
Innovation Center, Fudan University, Shanghai 200433, China
| | - Xianfeng Chen
- School
of Engineering, Institute for Bioengineering, University of Edinburgh, The King’s Buildings, Edinburgh EH9 3JL, U.K.
| | - Norbert Radacsi
- School
of Engineering, Institute for Materials and Processes, University of Edinburgh, Robert Stevenson Road, Edinburgh EH9 3FB, U.K.
- School
of Engineering, Institute for Bioengineering, University of Edinburgh, The King’s Buildings, Edinburgh EH9 3JL, U.K.
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3
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Qiang M, Chen Z, Liu H, Dong J, Gong K, Zhang X, Huo P, Zhu J, Shao Y, Ma J, Zhang B, Liu W, Tang M. Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting. Front Pharmacol 2025; 16:1516583. [PMID: 40041495 PMCID: PMC11877449 DOI: 10.3389/fphar.2025.1516583] [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: 10/24/2024] [Accepted: 01/27/2025] [Indexed: 03/06/2025] Open
Abstract
Owing to its high mortality rate, lung cancer (LC) remains the most common cancer worldwide, with the highest malignancy diagnosis rate. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling (PAM) pathway is a critical intracellular pathway involved in various cellular functions and regulates numerous cellular processes, including growth, survival, proliferation, metabolism, apoptosis, invasion, and angiogenesis. This review aims to highlight preclinical and clinical studies focusing on the PAM signaling pathway in LC and underscore the potential of natural products targeting it. Additionally, this review synthesizes the existing literature and discusses combination therapy and future directions for LC treatment while acknowledging the ongoing challenges in the field. Continuous development of novel therapeutic agents, technologies, and precision medicine offers an increasingly optimistic outlook for the treatment of LC.
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Affiliation(s)
- Min Qiang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Zhe Chen
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Hongyang Liu
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Junxue Dong
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Kejian Gong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xinjun Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Peng Huo
- Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, Germany
| | - Jingjun Zhu
- Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yifeng Shao
- Department of General Surgery, Capital Institute of Pediatrics’ Children’s Hospital, Beijing, China
| | - Jinazun Ma
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Bowei Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Wei Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Mingbo Tang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
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4
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Jain A, Das R, Giri M, Mane P, Shard A. Carbohydrate kinase inhibition: a promising strategy in cancer treatment. Drug Discov Today 2025; 30:104308. [PMID: 39912130 DOI: 10.1016/j.drudis.2025.104308] [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: 12/09/2024] [Revised: 01/21/2025] [Accepted: 01/30/2025] [Indexed: 02/07/2025]
Abstract
Carbohydrate kinases (CKs) are pivotal in various biological processes, including energy consumption, cell signaling, and biosynthesis. They are a group of enzymes that facilitate the phosphorylation of carbohydrates, playing a crucial role in cellular metabolism. These enzymes facilitate the transfer of a phosphate group from a high-energy donor like ATP to a specified location on a carbohydrate substrate. Dysregulated kinase activity drives tumor growth and progression. Inhibitors targeting these enzymes have been developed and used in cancer therapy. The CK family encompasses three major types: hexokinases, ribokinases, and phosphatidylinositol kinases, with inhibitors of paramount importance in cancer treatment. This review explores the role of CKs in cancer and its inhibitors, providing insights into improving existing inhibitors and designing new ones.
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Affiliation(s)
- Archit Jain
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Rudradip Das
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Muskan Giri
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Pranita Mane
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Amit Shard
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India.
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5
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Maruyama K, Shimizu Y, Nomura Y, Oh-Hara T, Takahashi Y, Nagayama S, Fujita N, Katayama R. Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization. NPJ Precis Oncol 2025; 9:4. [PMID: 39762482 PMCID: PMC11704227 DOI: 10.1038/s41698-024-00793-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
KRAS-specific inhibitors have shown promising antitumor effects, especially in non-small cell lung cancer, but limited efficacy in colorectal cancer (CRC) patients. Recent studies have shown that EGFR-mediated adaptive feedback mediates primary resistance to KRAS inhibitors, but the other resistance mechanisms have not been identified. In this study, we investigated intrinsic resistance mechanisms to KRAS inhibitors using patient-derived CRC cells (CRC-PDCs). We found that KRAS-mutated CRC-PDCs can be divided into at least an EGFR pathway-activated group and a PI3K/AKT pathway-activated group. In the latter group, PDCs with PIK3CA major mutation showed high sensitivity to PI3K+mTOR co-inhibition, and a PDC with Her2 amplification with PIK3CA minor mutation showed PI3K-AKT pathway dependency but lost KRAS-MAPK dependency by cytoplasmic localization of KRAS. In the PDC, Her2 knockout restored KRAS plasma membrane localization and KRAS inhibitor sensitivity. The current study provides insight into the mechanisms of primary resistance to KRAS inhibitors, including aberrant KRAS localization.
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Affiliation(s)
- Kohei Maruyama
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Yuki Shimizu
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yumi Nomura
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama, Japan
- Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tomoko Oh-Hara
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuki Takahashi
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama, Japan
- Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoshi Nagayama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Surgery, Uji-Tokushukai Medical Center, Kyoto, Japan
| | - Naoya Fujita
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ryohei Katayama
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
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6
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Kubota Y, Kimura S. Current Understanding of the Role of Autophagy in the Treatment of Myeloid Leukemia. Int J Mol Sci 2024; 25:12219. [PMID: 39596291 PMCID: PMC11594995 DOI: 10.3390/ijms252212219] [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: 09/29/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
The most important issues in acute myeloid leukemia are preventing relapse and treating relapse. Although the remission rate has improved to approximately 80%, the 5-year survival rate is only around 30%. The main reasons for this are the high relapse rate and the limited treatment options. In chronic myeloid leukemia patients, when a deep molecular response is achieved for a certain period of time through tyrosine kinase inhibitor treatment, about half of them will reach treatment-free remission, but relapse is still a problem. Therefore, potential therapeutic targets for myeloid leukemias are eagerly awaited. Autophagy suppresses the development of cancer by maintaining cellular homeostasis; however, it also promotes cancer progression by helping cancer cells survive under various metabolic stresses. In addition, autophagy is promoted or suppressed in cancer cells by various genetic mutations. Therefore, the development of therapies that target autophagy is also being actively researched in the field of leukemia. In this review, studies of the role of autophagy in hematopoiesis, leukemogenesis, and myeloid leukemias are presented, and the impact of autophagy regulation on leukemia treatment and the clinical trials of autophagy-related drugs to date is discussed.
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MESH Headings
- Humans
- Autophagy
- Animals
- Leukemia, Myeloid/pathology
- Leukemia, Myeloid/genetics
- Leukemia, Myeloid/therapy
- Leukemia, Myeloid/metabolism
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/drug therapy
- Antineoplastic Agents/therapeutic use
- Antineoplastic Agents/pharmacology
- Hematopoiesis
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Affiliation(s)
- Yasushi Kubota
- Department of Clinical Laboratory Medicine, Saga-Ken Medical Centre Koseikan, Saga 840-8571, Japan
| | - Shinya Kimura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan;
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7
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Lian S, Du Z, Chen Q, Xia Y, Miao X, Yu W, Sun Q, Feng C. From lab to clinic: The discovery and optimization journey of PI3K inhibitors. Eur J Med Chem 2024; 277:116786. [PMID: 39180946 DOI: 10.1016/j.ejmech.2024.116786] [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: 07/24/2024] [Revised: 08/13/2024] [Accepted: 08/15/2024] [Indexed: 08/27/2024]
Abstract
PI3K inhibitors have emerged as promising therapeutic agents due to their critical role in various cellular processes, particularly in cancer, where the PI3K pathway is frequently dysregulated. This review explores the evolutionary path of PI3K inhibitors from laboratory discovery to clinical application. The journey begins with early laboratory investigations into PI3K signaling and inhibitor development, highlighting fundamental discoveries that laid the foundation for subsequent advancements. Optimization strategies, including medicinal chemistry approaches and structural modifications, are scrutinized for their contributions to enhancing inhibitor potency, selectivity, and pharmacokinetic properties. The translation from preclinical studies to clinical trials is examined, emphasizing pivotal trials that evaluated efficacy and safety profiles. Challenges encountered during clinical development are critically assessed. Finally, the review discusses ongoing research directions and prospects for PI3K inhibitors, underscoring these agents' continuous evolution and therapeutic potential.
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Affiliation(s)
- Siyu Lian
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhenhua Du
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qingqing Chen
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu Xia
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xinxin Miao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Weiwei Yu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Qian Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Chong Feng
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
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8
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Gupta I, Gaykalova DA. Unveiling the role of PIK3R1 in cancer: A comprehensive review of regulatory signaling and therapeutic implications. Semin Cancer Biol 2024; 106-107:58-86. [PMID: 39197810 DOI: 10.1016/j.semcancer.2024.08.004] [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: 05/07/2024] [Revised: 07/11/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024]
Abstract
Phosphoinositide 3-kinase (PI3K) is responsible for phosphorylating phosphoinositides to generate secondary signaling molecules crucial for regulating various cellular processes, including cell growth, survival, and metabolism. The PI3K is a heterodimeric enzyme complex comprising of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85). The binding of the regulatory subunit, p85, with the catalytic subunit, p110, forms an integral component of the PI3K enzyme. PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) belongs to class IA of the PI3K family. PIK3R1 exhibits structural complexity due to alternative splicing, giving rise to distinct isoforms, prominently p85α and p55α. While the primary p85α isoform comprises multiple domains, including Src homology 3 (SH3) domains, a Breakpoint Cluster Region Homology (BH) domain, and Src homology 2 (SH2) domains (iSH2 and nSH2), the shorter isoform, p55α, lacks certain domains present in p85α. In this review, we will highlight the intricate regulatory mechanisms governing PI3K signaling along with the impact of PIK3R1 alterations on cellular processes. We will further delve into the clinical significance of PIK3R1 mutations in various cancer types and their implications for prognosis and treatment outcomes. Additionally, we will discuss the evolving landscape of targeted therapies aimed at modulating PI3K-associated pathways. Overall, this review will provide insights into the dynamic interplay of PIK3R1 in cancer, fostering advancements in precision medicine and the development of targeted interventions.
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Affiliation(s)
- Ishita Gupta
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA
| | - Daria A Gaykalova
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
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9
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Xanthopoulou E, Lamprou I, Mitrakas AG, Michos GD, Zois CE, Giatromanolaki A, Harris AL, Koukourakis MI. Autophagy Blockage Up-Regulates HLA-Class-I Molecule Expression in Lung Cancer and Enhances Anti-PD-L1 Immunotherapy Efficacy. Cancers (Basel) 2024; 16:3272. [PMID: 39409895 PMCID: PMC11476265 DOI: 10.3390/cancers16193272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND/OBJECTIVES Immune checkpoint inhibitors have an established role in non-small cell lung cancer (NSCLC) therapy. The loss of HLA-class-I expression allows cancer cell evasion from immune surveillance, disease progression, and failure of immunotherapy. The restoration of HLA-class-I expression may prove to be a game-changer in current immunotherapy strategies. Autophagic activity has been recently postulated to repress HLA-class-I expression in cancer cells. METHODS NSCLC cell lines (A549 and H1299) underwent late-stage (chloroquine and bafilomycin) and early-stage autophagy blockage (ULK1 inhibitors and MAP1LC3A silencing). The HLA-class-I expression was assessed with flow cytometry, a Western blot, and RT-PCR. NSCLC tissues were examined for MAP1LC3A and HLA-class-I expression using double immunohistochemistry. CD8+ T-cell cytotoxicity was examined in cancer cells pre-incubated with chloroquine and anti-PD-L1 monoclonal antibodies (Moabs); Results: A striking increase in HLA-class-I expression following incubation with chloroquine, bafilomycin, and IFNγ was noted in A549 and H1299 cancer cells, respectively. This effect was further confirmed in CD133+ cancer stem cells. HLA-class-I, β2-microglobulin, and TAP1 mRNA levels remained stable. Prolonged exposure to chloroquine further enhanced HLA-class-I expression. Similar results were noted following exposure to a ULK1 and a PIKfyve inhibitor. Permanent silencing of the MAP1LC3A gene resulted in enhanced HLA-class-I expression. In immunohistochemistry experiments, double LC3A+/HLA-class-I expression was seldom. Pre-incubation of H1299 cancer cells with chloroquine and anti-PD-L1 MoAbs increased the mean % of apoptotic/necrotic cells from 2.5% to 18.4%; Conclusions: Autophagy blockers acting either at late or early stages of the autophagic process may restore HLA-class-I-mediated antigen presentation, eventually leading to enhanced immunotherapy efficacy.
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Affiliation(s)
- Erasmia Xanthopoulou
- Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (I.L.); (A.G.M.); (G.D.M.); (C.E.Z.)
| | - Ioannis Lamprou
- Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (I.L.); (A.G.M.); (G.D.M.); (C.E.Z.)
| | - Achilleas G. Mitrakas
- Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (I.L.); (A.G.M.); (G.D.M.); (C.E.Z.)
| | - Georgios D. Michos
- Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (I.L.); (A.G.M.); (G.D.M.); (C.E.Z.)
| | - Christos E. Zois
- Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (I.L.); (A.G.M.); (G.D.M.); (C.E.Z.)
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK;
| | - Alexandra Giatromanolaki
- Department of Pathology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Adrian L. Harris
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK;
| | - Michael I. Koukourakis
- Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (I.L.); (A.G.M.); (G.D.M.); (C.E.Z.)
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10
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Qian C, Li X, Zhang J, Wang Y. Small Molecular Inhibitors That Target ATM for Drug Discovery: Current Research and Potential Prospective. J Med Chem 2024; 67:14742-14767. [PMID: 39149790 DOI: 10.1021/acs.jmedchem.4c01064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
The protein kinase ataxia telangiectasia mutated (ATM) is a constituent of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, exerting a pivotal influence on diverse cellular processes, notably the signaling of double-strand DNA breaks (DSB) and stress response. The dysregulation of ATM is implicated in the pathogenesis of cancer and other diseases such as neurodegeneration. Hence, ATM is deemed a promising candidate for potential therapeutic interventions across a spectrum of diseases. Presently, while ATM small molecule inhibitors are not commercially available, various selective inhibitors have progressed to the clinical research phase. Specifically, AZD1390, WSD0628, SYH2051, and ZN-B-2262 are under investigation in clinical studies pertaining to glioblastoma multiforme and advanced solid tumors, respectively. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of ATM. Subsequently, we concentrate on the design concepts and structure-activity relationships (SAR) of ATM inhibitors, delineating potential avenues for the development of more efficacious ATM-targeted inhibitors.
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Affiliation(s)
- Chunlin Qian
- Department of Respiratory and Critical Care Medicine and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and State Key Laboratory of Respiratory Health and Multimorbidity and Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, Sichuan China
| | - Xiaoxue Li
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan China
| | - Jifa Zhang
- Department of Respiratory and Critical Care Medicine and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and State Key Laboratory of Respiratory Health and Multimorbidity and Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, Sichuan China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan China
| | - Yuxi Wang
- Department of Respiratory and Critical Care Medicine and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and State Key Laboratory of Respiratory Health and Multimorbidity and Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, Sichuan China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan China
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11
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Hong CR, Liew LP, Wong WW, Dickson BD, Cheng G, Shome A, Airey R, Jaiswal J, Lipert B, Jamieson SMF, Wilson WR, Hay MP. Identification of 6-Anilino Imidazo[4,5- c]pyridin-2-ones as Selective DNA-Dependent Protein Kinase Inhibitors and Their Application as Radiosensitizers. J Med Chem 2024; 67:12366-12385. [PMID: 39007759 DOI: 10.1021/acs.jmedchem.4c01120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5-c]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 78 as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells. Compound 78 demonstrated robust radiosensitization of a broad range of cancer cells in vitro, displayed high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C) and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts to radiation. Compound 78 also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound 78 represents a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for cancer treatment.
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Affiliation(s)
- Cho R Hong
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Lydia P Liew
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Way W Wong
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Benjamin D Dickson
- Chemistry and Applied Physics, School of Science, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand
| | - Gary Cheng
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Avik Shome
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Rebecca Airey
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Jagdish Jaiswal
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Barbara Lipert
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Stephen M F Jamieson
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - William R Wilson
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Michael P Hay
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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12
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Han S, Zhuang H, Diao Y, Segal M, Tithi TI, Zhang W, Reeves WH. Altered lipid homeostasis and autophagy precipitate diffuse alveolar hemorrhage in murine lupus. AUTOPHAGY REPORTS 2024; 3:2379193. [PMID: 39871963 PMCID: PMC11772013 DOI: 10.1080/27694127.2024.2379193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 07/01/2024] [Accepted: 07/05/2024] [Indexed: 01/29/2025]
Abstract
Abnormal autophagy regulation is implicated in lupus and other autoimmune diseases. We investigated autophagy in the murine pristane-induced lupus model. Pristane causes monocyte/macrophage-mediated endoplasmic reticulum (ER) stress in lung endothelial cells and diffuse alveolar hemorrhage (DAH) indistinguishable from DAH in lupus patients. Enlarged macrophages with abundant lipid droplets containing neutral lipid and exhibiting increased autophagosome staining were observed in the lung and peritoneal macrophages after pristane treatment. Cellular overload of neutral lipid can lead to selective autophagy (lipophagy) of lipid droplets and transport to lysosomes. The autophagy inducer rapamycin decreased neutral lipid staining but aggravated DAH, while an autophagy inhibitor (3-methyladenine) blocked the onset of DAH. Pristane-induced autophagy in macrophages was confirmed by acridine orange assay and LC3 western blot. Pristane also enlarged lysosomal volume and enhanced cathepsin S, D, and K expression while decreasing lysosomal acid lipase activity. If the capacity to degrade neutral lipid into free cholesterol and fatty acids is overwhelmed, lysosomes enlarge and can release cathepsins into the cytoplasm promoting cell death. Increasing lysosomal cholesterol content by blocking the Niemann-Pick C disease protein NPC1 protects against lysosome-dependent cell death. Treatment with NPC1 inhibitors U18666A or cepharanthine, which stabilize lysosomes, normalized lysosomal volume, reversed ER stress, and prevented DAH in pristane-treated mice. We conclude that pristane disrupts lipid homeostasis, promoting autophagy, lysosomal dysfunction, ER stress, and cell death leading to DAH. NPC1 inhibition reverses these abnormalities, preventing DAH. The findings shed light on the role of autophagy and lysosomal dysfunction in the pathogenesis of lupus.
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Affiliation(s)
- Shuhong Han
- Division of Rheumatology, Allergy, & Clinical Immunology
| | - Haoyang Zhuang
- Division of Rheumatology, Allergy, & Clinical Immunology
| | - Yanpeng Diao
- Division of Nephrology, Hypertension, and Renal Transplantation
| | - Mark Segal
- Division of Nephrology, Hypertension, and Renal Transplantation
| | - Tanzia Islam Tithi
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL32610
| | - Weizhou Zhang
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL32610
| | - Westley H. Reeves
- Division of Rheumatology, Allergy, & Clinical Immunology
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL32610
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13
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Kelly LM, Rutter JC, Lin KH, Ling F, Duchmann M, Latour E, Arang N, Pasquer H, Ho Nhat D, Charles J, Killarney ST, Ang HX, Namor F, Culeux C, Lombard B, Loew D, Swaney DL, Krogan NJ, Brunel L, Carretero É, Verdié P, Amblard M, Fodil S, Huynh T, Sebert M, Adès L, Raffoux E, Fenouille N, Itzykson R, Lobry C, Benajiba L, Forget A, Martin AR, Wood KC, Puissant A. Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule. NATURE CANCER 2024; 5:1082-1101. [PMID: 38816660 PMCID: PMC11778622 DOI: 10.1038/s43018-024-00782-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 05/13/2024] [Indexed: 06/01/2024]
Abstract
Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.
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Affiliation(s)
- Lois M Kelly
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Justine C Rutter
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Kevin H Lin
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Frank Ling
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Matthieu Duchmann
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Emmanuelle Latour
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Nadia Arang
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
| | - Hélène Pasquer
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Duong Ho Nhat
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Juliette Charles
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Shane T Killarney
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Hazel X Ang
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Federica Namor
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Cécile Culeux
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Bérangère Lombard
- Curie Institute, Mass Spectrometry and Proteomics Facility, PSL Research University, Paris, France
| | - Damarys Loew
- Curie Institute, Mass Spectrometry and Proteomics Facility, PSL Research University, Paris, France
| | - Danielle L Swaney
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
- Gladstone Institutes, San Francisco, California, USA
| | - Nevan J Krogan
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
- Gladstone Institutes, San Francisco, California, USA
| | - Luc Brunel
- IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France
| | - Élodie Carretero
- IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France
| | - Pascal Verdié
- IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France
| | - Muriel Amblard
- IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France
| | - Sofiane Fodil
- Department of Hematology and Immunology, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France
| | - Tony Huynh
- Department of Hematology and Immunology, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France
| | - Marie Sebert
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
- Department of Hematology and Immunology, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France
| | - Lionel Adès
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
- Department of Hematology and Immunology, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France
| | - Emmanuel Raffoux
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
- Department of Hematology and Immunology, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France
| | - Nina Fenouille
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Raphaël Itzykson
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
- Department of Hematology and Immunology, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France
| | - Camille Lobry
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
| | - Lina Benajiba
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France
- Clinical Investigation Center, Saint-Louis Hospital, AP-HP, Paris Cité University, Paris, France
| | - Antoine Forget
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
| | - Anthony R Martin
- IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France.
| | - Kris C Wood
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
| | - Alexandre Puissant
- INSERM UMR 944, IRSL, Saint-Louis Hospital, Paris Cité University, Paris, France.
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14
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Martínez-Pérez J, Torrado C, Domínguez-Cejudo MA, Valladares-Ayerbes M. Targeted Treatment against Cancer Stem Cells in Colorectal Cancer. Int J Mol Sci 2024; 25:6220. [PMID: 38892410 PMCID: PMC11172446 DOI: 10.3390/ijms25116220] [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: 04/27/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
The cancer stem cell (SC) theory proposes that a population of SCs serves as the driving force behind fundamental tumor processes, including metastasis, recurrence, and resistance to therapy. The standard of care for patients with stage III and high-risk stage II colorectal cancer (CRC) includes surgery and adjuvant chemotherapy. Fluoropyrimidines and their combination with oxaliplatin increased the cure rates, being able to eradicate the occult metastatic SC in a fraction of patients. The treatment for unresectable metastatic CRC is based on chemotherapy, antibodies to VEGF and EGFR, and tyrosine-kinase inhibitors. Immunotherapy is used in MSI-H tumors. Currently used drugs target dividing cells and, while often effective at debulking tumor mass, these agents have largely failed to cure metastatic disease. SCs are generated either due to genetic and epigenetic alterations in stem/progenitor cells or to the dedifferentiation of somatic cells where diverse signaling pathways such as Wnt/β-catenin, Hedgehog, Notch, TGF-β/SMAD, PI3K/Akt/mTOR, NF-κB, JAK/STAT, DNA damage response, and Hippo-YAP play a key role. Anti-neoplastic treatments could be improved by elimination of SCs, becoming an attractive target for the design of novel agents. Here, we present a review of clinical trials assessing the efficacy of targeted treatment focusing on these pathways in CRC.
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Affiliation(s)
- Julia Martínez-Pérez
- Medical Oncology Department, Hospital Universitario Virgen del Rocio (HUVR), Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
| | - Carlos Torrado
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - María A. Domínguez-Cejudo
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
| | - Manuel Valladares-Ayerbes
- Medical Oncology Department, Hospital Universitario Virgen del Rocio (HUVR), Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
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15
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Gilmer TM, Lai CH, Guo K, Deland K, Ashcraft KA, Stewart AE, Wang Y, Fu J, Wood KC, Kirsch DG, Kastan MB. A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors. Mol Cancer Ther 2024; 23:751-765. [PMID: 38588408 DOI: 10.1158/1535-7163.mct-23-0890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/27/2024] [Accepted: 03/25/2024] [Indexed: 04/10/2024]
Abstract
A majority of patients with cancer receive radiotherapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiotherapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses to DNA breaks introduced by radiation or other cancer therapies have been gained in recent years and approaches to manipulate these responses to enhance tumor cell killing or reduce normal tissue toxicity are of great interest. Here, we report the identification and initial characterization of XRD-0394, a potent and specific dual inhibitor of two DNA damage response kinases, ATM and DNA-PKcs. This orally bioavailable molecule demonstrates significantly enhanced tumor cell kill in the setting of therapeutic ionizing irradiation in vitro and in vivo. XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro. In addition, in cells lacking BRCA1/2 XRD-0394 shows single-agent activity and synergy in combination with PARP inhibitors. A phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with radiotherapy has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with radiotherapy, PARP inhibitors, and targeted delivery of topoisomerase I inhibitors.
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Affiliation(s)
| | - Chun-Hsiang Lai
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - Kexiao Guo
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - Katherine Deland
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Kathleen A Ashcraft
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Amy E Stewart
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | | | | | - Kris C Wood
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - David G Kirsch
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Michael B Kastan
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
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16
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Rios SA, Oyervides S, Uribe D, Reyes AM, Fanniel V, Vazquez J, Keniry M. Emerging Therapies for Glioblastoma. Cancers (Basel) 2024; 16:1485. [PMID: 38672566 PMCID: PMC11048459 DOI: 10.3390/cancers16081485] [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: 02/16/2024] [Revised: 04/01/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Glioblastoma is most commonly a primary brain tumor and the utmost malignant one, with a survival rate of approximately 12-18 months. Glioblastoma is highly heterogeneous, demonstrating that different types of cells from the same tumor can manifest distinct gene expression patterns and biological behaviors. Conventional therapies such as temozolomide, radiation, and surgery have limitations. As of now, there is no cure for glioblastoma. Alternative treatment methods to eradicate glioblastoma are discussed in this review, including targeted therapies to PI3K, NFKβ, JAK-STAT, CK2, WNT, NOTCH, Hedgehog, and TGFβ pathways. The highly novel application of oncolytic viruses and nanomaterials in combating glioblastoma are also discussed. Despite scores of clinical trials for glioblastoma, the prognosis remains poor. Progress in breaching the blood-brain barrier with nanomaterials and novel avenues for targeted and combination treatments hold promise for the future development of efficacious glioblastoma therapies.
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Affiliation(s)
| | | | | | | | | | | | - Megan Keniry
- School of Integrative Biological and Chemical Sciences, College of Sciences, The University of Texas Rio Grande Valley, Edinburg, TX 78539, USA; (S.A.R.); (D.U.); (A.M.R.)
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17
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Leiphrakpam PD, Are C. PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment. Int J Mol Sci 2024; 25:3178. [PMID: 38542151 PMCID: PMC10970097 DOI: 10.3390/ijms25063178] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/02/2024] [Accepted: 03/05/2024] [Indexed: 11/11/2024] Open
Abstract
In the last decade, pathway-specific targeted therapy has revolutionized colorectal cancer (CRC) treatment strategies. This type of therapy targets a tumor-vulnerable spot formed primarily due to an alteration in an oncogene and/or a tumor suppressor gene. However, tumor heterogeneity in CRC frequently results in treatment resistance, underscoring the need to understand the molecular mechanisms involved in CRC for the development of novel targeted therapies. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/Akt/mTOR) signaling pathway axis is a major pathway altered in CRC. The aberrant activation of this pathway is associated with CRC initiation, progression, and metastasis and is critical for the development of drug resistance in CRC. Several drugs target PI3K/Akt/mTOR in clinical trials, alone or in combination, for the treatment of CRC. This review aims to provide an overview of the role of the PI3K/Akt/mTOR signaling pathway axis in driving CRC, existing PI3K/Akt/mTOR-targeted agents against CRC, their limitations, and future trends.
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Affiliation(s)
- Premila D. Leiphrakpam
- Graduate Medical Education, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Surgical Oncology, Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chandrakanth Are
- Graduate Medical Education, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Surgical Oncology, Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
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18
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Hu J, Fu S, Zhan Z, Zhang J. Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects. Eur J Med Chem 2024; 265:116109. [PMID: 38183777 DOI: 10.1016/j.ejmech.2023.116109] [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: 12/05/2023] [Revised: 12/24/2023] [Accepted: 12/28/2023] [Indexed: 01/08/2024]
Abstract
Phosphoinositide 3-kinases (PI3Ks) modify lipids by the phosphorylation of inositol phospholipids at the 3'-OH position, thereby participating in signal transduction and exerting effects on various physiological processes such as cell growth, metabolism, and organism development. PI3K activation also drives cancer cell growth, survival, and metabolism, with genetic dysregulation of this pathway observed in diverse human cancers. Therefore, this target is considered a promising potential therapeutic target for various types of cancer. Currently, several selective PI3K inhibitors and one dual-target PI3K inhibitor have been approved and launched on the market. However, the majority of these inhibitors have faced revocation or voluntary withdrawal of indications due to concerns regarding their adverse effects. This article provides a comprehensive review of the structure and biological functions, and clinical status of PI3K inhibitors, with a specific emphasis on the development strategies and structure-activity relationships of dual-target PI3K inhibitors. The findings offer valuable insights and future directions for the development of highly promising dual-target drugs targeting PI3K.
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Affiliation(s)
- Jiarui Hu
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Siyu Fu
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Zixuan Zhan
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jifa Zhang
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
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19
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Nie S, Chang L, Huang Y, Zhou H, Yang Q, Kong L, Li Y. β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K. NATURAL PRODUCTS AND BIOPROSPECTING 2024; 14:3. [PMID: 38169019 PMCID: PMC10761647 DOI: 10.1007/s13659-023-00422-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 11/22/2023] [Indexed: 01/05/2024]
Abstract
Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC50 value of 4.28 µM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.
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Affiliation(s)
- Shiyun Nie
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Lizhong Chang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Ying Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Heyang Zhou
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Qianqing Yang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Lingmei Kong
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.
| | - Yan Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.
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20
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Ihlamur M, Akgul B, Zengin Y, Korkut ŞV, Kelleci K, Abamor EŞ. The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches. Curr Mol Med 2024; 24:478-494. [PMID: 37165594 DOI: 10.2174/1566524023666230509161645] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 02/03/2023] [Accepted: 02/07/2023] [Indexed: 05/12/2023]
Abstract
mTOR is a serine/threonine kinase that plays various roles in cell growth, proliferation, and metabolism. mTOR signaling in cancer becomes irregular. Therefore, drugs targeting mTOR have been developed. Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Therefore, new inhibition approaches are developed. Although these new inhibition approaches have not been widely investigated in cancer treatment, the use of nanoparticles has been evaluated as a new treatment option in a few types of cancer. This review outlines the functions of mTOR in the cancer process, its resistance mechanisms, and the efficiency of mTOR inhibitors in cancer treatment. Furthermore, it discusses the next-generation mTOR inhibitors and inhibition strategies created using nanoparticles. Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness.
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Affiliation(s)
- Murat Ihlamur
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
- Department of Electronics and Automation, Biruni University, Istanbul, Turkey
| | - Busra Akgul
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
| | - Yağmur Zengin
- Biomedical Engineering Institute, Department of Biomedical Engineering, Bogazici University, Istanbul, Turkey
| | - Şenay Vural Korkut
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Yildiz Technical University, Istanbul, Turkey
| | - Kübra Kelleci
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
- Department of Medical Services and Techniques, Beykoz University, Istanbul, Turkey
| | - Emrah Şefik Abamor
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
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21
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Park YS, kim J, Ryu YS, moon JH, shin YJ, kim JH, hong SW, jung SA, lee S, kim SM, lee DH, kim DY, yun H, you JE, yoon DI, kim CH, koh DI, jin DH. Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer. Cancer Biol Ther 2023; 24:2246208. [PMID: 37621144 PMCID: PMC10461515 DOI: 10.1080/15384047.2023.2246208] [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: 09/07/2022] [Revised: 02/07/2023] [Accepted: 06/02/2023] [Indexed: 08/26/2023] Open
Abstract
Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified PIK3CA mutant (PIK3CA MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in PIK3CA wild type (PIK3CA WT) cell lines, while PIK3CA MT cells did not respond to SMI-4a in cell death assays. In vivo xenograft and PDX experiments confirmed that PIK3CA MT is responsible for the resistance to SMI-4a. Inhibition of PIK3CA MT by PI3K inhibitors restored SMI-4a sensitivity in PIK3CA MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the PIK3CA genotype and that co-targeting of PI3K and PIM1 in PIK3CA MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients.
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Affiliation(s)
- Yoon Sun Park
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joseph kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yea Seong Ryu
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Jai-Hee moon
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Yu Jin shin
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Jeong Hee kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Seung-Woo hong
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Soo-A jung
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Seul lee
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Seung-Mi kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Dae Hee lee
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Do Yeon kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyeseon yun
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ji-Eun you
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong Il yoon
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chul Hee kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-In koh
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Dong-Hoon jin
- Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Convergence Medicine, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
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22
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Guzmán EA, Peterson TA, Wright AE. The Marine Natural Compound Dragmacidin D Selectively Induces Apoptosis in Triple-Negative Breast Cancer Spheroids. Mar Drugs 2023; 21:642. [PMID: 38132962 PMCID: PMC10871089 DOI: 10.3390/md21120642] [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: 11/14/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 12/23/2023] Open
Abstract
Cancer cells grown in 3D spheroid cultures are considered more predictive for clinical efficacy. The marine natural product dragmacidin D induces apoptosis in MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) spheroids within 24 h of treatment while showing no cytotoxicity against the same cells grown in monolayers and treated for 72 h. The IC50 for cytotoxicity based on caspase 3/7 cleavage in the spheroid assay was 8 ± 1 µM in MDA-MB-231 cells and 16 ± 0.6 µM in MDA-MB-468 cells at 24 h. No cytotoxicity was seen at all in 2D, even at the highest concentration tested. Thus, the IC50 for cytotoxicity in the MTT assay (2D) in these cells was found to be >75 µM at 72 h. Dragmacidin D exhibited synergy when used in conjunction with paclitaxel, a current treatment for TNBC. Studies into the signaling changes using a reverse-phase protein array showed that treatment with dragmacidin D caused significant decreases in histones. Differential protein expression was used to hypothesize that its potential mechanism of action involves acting as a protein synthesis inhibitor or a ribonucleotide reductase inhibitor. Further testing is necessary to validate this hypothesis. Dragmacidin D also caused a slight decrease in an invasion assay in the MDA-MB-231 cells, although this failed to be statistically significant. Dragmacidin D shows intriguing selectivity for spheroids and has the potential to be a treatment option for triple-negative breast cancer, which merits further research into understanding this activity.
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Affiliation(s)
- Esther A. Guzmán
- Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute, Florida Atlantic University, 5600 US 1 North, Fort Pierce, FL 34946, USA; (T.A.P.); (A.E.W.)
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23
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Chen X, Zhang T, Ren X, Wei Y, Zhang X, Zang X, Ju X, Qin C, Xu D. CHKB-AS1 enhances proliferation and resistance to NVP-BEZ235 of renal cancer cells via regulating the phosphorylation of MAP4 and PI3K/AKT/mTOR signaling. Eur J Med Res 2023; 28:588. [PMID: 38093375 PMCID: PMC10720114 DOI: 10.1186/s40001-023-01558-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/29/2023] [Indexed: 12/17/2023] Open
Abstract
Targeted therapy is pivotal in renal carcinoma treatment, and the dual-inhibitor NVP-BEZ235 has emerged as a promising candidate in preliminary studies. Its effectiveness against renal carcinoma and the mechanisms underlying potential resistance, however, warrant further exploration. This study aims to elucidate these aspects, enhancing our understanding of NVP-BEZ235's future clinical utility. To investigate resistance mechanisms, renal cancer cell lines were exposed to progressively increasing concentrations of NVP-BEZ235, leading to the development of stable resistance. These resistant cells underwent extensive RNA-sequencing analysis. We implemented gene interference techniques using plasmid vectors and lentivirus and conducted regular IC50 assessments. To pinpoint the role of LncRNAs, we utilized FISH and immunofluorescence staining assays, supplemented by RNA pull-down and RIP assays to delineate interactions between LncRNA and its RNA-binding protein (RBP). Further, Western blotting and qRT-PCR were employed to examine alterations in signaling pathways, with an animal model providing additional validation. Our results show a marked increase in the IC50 of NVP-BEZ235 in resistant cell lines compared to their parental counterparts. A significant revelation was the role of LncRNA-CHKB-AS1 in mediating drug resistance. We observed dysregulated expression of CHKB-AS1 in both clinical samples of clear cell renal cell carcinoma (ccRCC) and cell lines. In vivo experiments further substantiated our findings, showing that CHKB-AS1 overexpression significantly enhanced tumor growth and resistance to NVP-BEZ235 in a subcutaneous tumorigenesis model, as evidenced by increased tumor volume and weight, whereas CHKB-AS1 knockdown led to a marked reduction in these parameters. Critically, CHKB-AS1 was identified to interact with MAP4, a key regulator in the phosphorylation of the PI3k/Akt/mTOR pathway. This interaction contributes to a diminished antitumor effect of NVP-BEZ235, highlighting the intricate mechanism through which CHKB-AS1 modulates drug resistance pathways, potentially impacting therapeutic strategies against renal carcinoma.
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Affiliation(s)
- Xinglin Chen
- Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New District, Shanghai, 201203, China
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, 210029, Jiangsu Province, China
| | - Tongtong Zhang
- Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New District, Shanghai, 201203, China
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, 210029, Jiangsu Province, China
| | - Xiaohan Ren
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, 210029, Jiangsu Province, China
| | - Yuang Wei
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, 210029, Jiangsu Province, China
| | - Xu Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, 210029, Jiangsu Province, China
| | - Xinyue Zang
- Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New District, Shanghai, 201203, China
| | - Xiran Ju
- Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
| | - Chao Qin
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, 210029, Jiangsu Province, China.
| | - Dongliang Xu
- Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
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24
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Li S, Chen JS, Li X, Bai X, Shi D. MNK, mTOR or eIF4E-selecting the best anti-tumor target for blocking translation initiation. Eur J Med Chem 2023; 260:115781. [PMID: 37669595 DOI: 10.1016/j.ejmech.2023.115781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/29/2023] [Accepted: 08/29/2023] [Indexed: 09/07/2023]
Abstract
Overexpression of eIF4E is common in patients with various solid tumors and hematologic cancers. As a potential anti-cancer target, eIF4E has attracted extensive attention from researchers. At the same time, mTOR kinases inhibitors and MNK kinases inhibitors, which are directly related to regulation of eIF4E, have been rapidly developed. To explore the optimal anti-cancer targets among MNK, mTOR, and eIF4E, this review provides a detailed classification and description of the anti-cancer activities of promising compounds. In addition, the structures and activities of some dual-target inhibitors are briefly described. By analyzing the different characteristics of the inhibitors, it can be concluded that MNK1/2 and eIF4E/eIF4G interaction inhibitors are superior to mTOR inhibitors. Simultaneous inhibition of MNK and eIF4E/eIF4G interaction may be the most promising anti-cancer method for targeting translation initiation.
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Affiliation(s)
- Shuo Li
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
| | - Jia-Shu Chen
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
| | - Xiangqian Li
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
| | - Xiaoyi Bai
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
| | - Dayong Shi
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
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25
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Shrestha R, McCann T, Saravanan H, Lieberth J, Koirala P, Bloomekatz J. The myocardium utilizes a platelet-derived growth factor receptor alpha (Pdgfra)-phosphoinositide 3-kinase (PI3K) signaling cascade to steer toward the midline during zebrafish heart tube formation. eLife 2023; 12:e85930. [PMID: 37921445 PMCID: PMC10651176 DOI: 10.7554/elife.85930] [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: 01/13/2023] [Accepted: 11/02/2023] [Indexed: 11/04/2023] Open
Abstract
Coordinated cell movement is a fundamental process in organ formation. During heart development, bilateral myocardial precursors collectively move toward the midline (cardiac fusion) to form the primitive heart tube. Extrinsic influences such as the adjacent anterior endoderm are known to be required for cardiac fusion. We previously showed however, that the platelet-derived growth factor receptor alpha (Pdgfra) is also required for cardiac fusion (Bloomekatz et al., 2017). Nevertheless, an intrinsic mechanism that regulates myocardial movement has not been elucidated. Here, we show that the phosphoinositide 3-kinase (PI3K) intracellular signaling pathway has an essential intrinsic role in the myocardium directing movement toward the midline. In vivo imaging further reveals midline-oriented dynamic myocardial membrane protrusions that become unpolarized in PI3K-inhibited zebrafish embryos where myocardial movements are misdirected and slower. Moreover, we find that PI3K activity is dependent on and interacts with Pdgfra to regulate myocardial movement. Together our findings reveal an intrinsic myocardial steering mechanism that responds to extrinsic cues during the initiation of cardiac development.
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Affiliation(s)
- Rabina Shrestha
- Department of Biology, University of MississippiUniversityUnited States
| | - Tess McCann
- Department of Biology, University of MississippiUniversityUnited States
| | - Harini Saravanan
- Department of Biology, University of MississippiUniversityUnited States
| | - Jaret Lieberth
- Department of Biology, University of MississippiUniversityUnited States
| | - Prashanna Koirala
- Department of Biology, University of MississippiUniversityUnited States
| | - Joshua Bloomekatz
- Department of Biology, University of MississippiUniversityUnited States
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26
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Yoo MJ, Choi J, Jang YJ, Park SY, Seol JW. Anti-cancer effect of palmatine through inhibition of the PI3K/AKT pathway in canine mammary gland tumor CMT-U27 cells. BMC Vet Res 2023; 19:223. [PMID: 37880653 PMCID: PMC10601335 DOI: 10.1186/s12917-023-03782-2] [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: 06/22/2023] [Accepted: 10/08/2023] [Indexed: 10/27/2023] Open
Abstract
Canine mammary gland tumors (CMTs) are the most common and lethal cancers in female dogs. Dysregulated phosphoinositide 3-kinases (PI3K)/AKT pathway reportedly was involved in the growth and metastasis of CMTs. However, there are few studies on therapeutic strategies for targeting the PI3K pathway in CMTs. In this study, we aimed to determine whether palmatine, a natural isoquinoline alkaloid with anti-cancer properties, could inhibit the growth of CMTs and whether the inhibitory effect was mediated through the PI3K/AKT pathway. Our in vitro experiments on CMT-U27, a CMT cell line, showed that palmatine reduced cell proliferation and induced cell death. Western blotting results revealed that palmatine decreased the protein expression of PI3K, PTEN, AKT, and mechanistic target of rapamycin in the PI3K/AKT pathway, which was supported by the results of immunocytochemistry. Additionally, palmatine suppressed the migration and tube formation of canine aortic endothelial cells as well as the migration of CMT U27 cells. Our in vivo results showed that palmatine inhibited tumor growth in a CMT-U27 mouse xenograft model. We observed a decreased expression of proteins in the PI3K/AKT pathway in tumor tissues, similar to the in vitro results. Furthermore, palmatine significantly disrupted the tumor vasculature and inhibited metastasis to adjacent lymph nodes. In conclusion, our findings demonstrate that palmatine exerts anti-cancer effects against CMTs by inhibiting PI3K/AKT signaling pathway, suggesting that palmatine has potential as a canine-specific PI3K inhibitor for the treatment of CMTs.
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Affiliation(s)
- Min-Jae Yoo
- College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeollabuk-Do, 54596, Republic of Korea
| | - Jawun Choi
- College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeollabuk-Do, 54596, Republic of Korea
| | - Ye-Ji Jang
- College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeollabuk-Do, 54596, Republic of Korea
| | - Sang-Youel Park
- College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeollabuk-Do, 54596, Republic of Korea
| | - Jae-Won Seol
- College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeollabuk-Do, 54596, Republic of Korea.
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27
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Dwivedi D, Harry D, Meraldi P. Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1. Nat Commun 2023; 14:6088. [PMID: 37773176 PMCID: PMC10541884 DOI: 10.1038/s41467-023-41753-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 09/18/2023] [Indexed: 10/01/2023] Open
Abstract
A tight synchrony between the DNA and centrosome cycle is essential for genomic integrity. Centriole disengagement, which licenses centrosomes for duplication, occurs normally during mitotic exit. We recently demonstrated that mild DNA replication stress typically seen in cancer cells causes premature centriole disengagement in untransformed mitotic human cells, leading to transient multipolar spindles that favour chromosome missegregation. How mild replication stress accelerates the centrosome cycle at the molecular level remained, however, unclear. Using ultrastructure expansion microscopy, we show that mild replication stress induces premature centriole disengagement already in G2 via the ATR-Chk1 axis of the DNA damage repair pathway. This results in a sub-critical Plk1 kinase activity that primes the pericentriolar matrix for Separase-dependent disassembly but is insufficient for rapid mitotic entry, causing premature centriole disengagement in G2. We postulate that the differential requirement of Plk1 activity for the DNA and centrosome cycles explains how mild replication stress disrupts the synchrony between both processes and contributes to genomic instability.
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Affiliation(s)
- Devashish Dwivedi
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Geneva, Switzerland
- Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Geneva, Switzerland
| | - Daniela Harry
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Geneva, Switzerland
- Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Geneva, Switzerland
| | - Patrick Meraldi
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Geneva, Switzerland.
- Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Geneva, Switzerland.
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28
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Liu J, Pan Y, Liu Y, Wei W, Hu X, Xin W, Chen N. The regulation of PTEN: Novel insights into functions as cancer biomarkers and therapeutic targets. J Cell Physiol 2023; 238:1693-1715. [PMID: 37334436 DOI: 10.1002/jcp.31053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023]
Abstract
This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3-kinases (PI3K)-protein kinase B-mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)-3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein-protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted.
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Affiliation(s)
- Jie Liu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yongli Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Yuheng Liu
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Xiaoping Hu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Wenqiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Nan Chen
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
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29
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Biswas H, Makinwa Y, Zou Y. Novel Cellular Functions of ATR for Therapeutic Targeting: Embryogenesis to Tumorigenesis. Int J Mol Sci 2023; 24:11684. [PMID: 37511442 PMCID: PMC10380702 DOI: 10.3390/ijms241411684] [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: 07/07/2023] [Revised: 07/14/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
The DNA damage response (DDR) is recognized as having an important role in cancer growth and treatment. ATR (ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has shown significant therapeutic potential in cancer treatment. ATR inhibitors have shown anti-tumor effectiveness, not just as monotherapies but also in enhancing the effects of standard chemotherapy, radiation, and immunotherapy. The biological basis of ATR is examined in this review, as well as its functional significance in the development and therapy of cancer, and the justification for inhibiting this target as a therapeutic approach, including an assessment of the progress and status of previous decades' development of effective and selective ATR inhibitors. The current applications of these inhibitors in preclinical and clinical investigations as single medicines or in combination with chemotherapy, radiation, and immunotherapy are also fully reviewed. This review concludes with some insights into the many concerns highlighted or identified with ATR inhibitors in both the preclinical and clinical contexts, as well as potential remedies proposed.
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Affiliation(s)
| | | | - Yue Zou
- Department of Cell and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (H.B.); (Y.M.)
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30
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Lu T, Li T, Wu MK, Zheng CC, He XM, Zhu HL, Li L, Man RJ. Molecular simulations required to target novel and potent inhibitors of cancer invasion. Expert Opin Drug Discov 2023; 18:1367-1377. [PMID: 37676052 DOI: 10.1080/17460441.2023.2254695] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 08/30/2023] [Indexed: 09/08/2023]
Abstract
INTRODUCTION Computer-aided drug design (CADD) is a computational approach used to discover, develop, and analyze drugs and active molecules with similar biochemical properties. Molecular simulation technology has significantly accelerated drug research and reduced manufacturing costs. It is an optimized drug discovery method that greatly improves the efficiency of novel drug development processes. AREASCOVERED This review discusses the development of molecular simulations of effective cancer inhibitors and traces the main outcomes of in silico studies by introducing representative categories of six important anticancer targets. The authors provide views on this topic from the perspective of both medicinal chemistry and artificial intelligence, indicating the major challenges and predicting trends. EXPERT OPINION The goal of introducing CADD into cancer treatment is to realize a highly efficient, accurate, and desired approach with a high success rate for identifying potent drug candidates. However, the major challenge is the lack of a sophisticated data-filtering mechanism to verify bottom data from mixed-quality references. Consequently, despite the continuous development of algorithms, computer power, and interface optimization, specific data filtering mechanisms will become an urgent and crucial issue in the future.
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Affiliation(s)
| | - Tong Li
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
| | - Meng-Ke Wu
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
| | - Chi-Chong Zheng
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
| | - Xue-Mei He
- Agro-food Science and Technology Research Institute, Guangxi Academy of Agricultural Science, Nanning, China
| | - Hai-Liang Zhu
- School of Life Sciences, Nanjing University, Nanjing, China
| | - Li Li
- Agro-food Science and Technology Research Institute, Guangxi Academy of Agricultural Science, Nanning, China
| | - Ruo-Jun Man
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
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Yang C, Chen Y, Wu T, Gao Y, Liu X, Yang Y, Ling Y, Jia Y, Deng M, Wang J, Zhou Y. Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K/mTOR dual inhibitor for the treatment of acute myeloid leukemia. Eur J Med Chem 2023; 258:115543. [PMID: 37329712 DOI: 10.1016/j.ejmech.2023.115543] [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: 04/14/2023] [Revised: 05/25/2023] [Accepted: 06/03/2023] [Indexed: 06/19/2023]
Abstract
PI3K-Akt-mTOR pathway is a highly activated signal transduction pathway in human hematological malignancies and has been validated as a promising target for acute myeloid leukemia (AML) therapy. Herein, we designed and synthesized a series of 7-azaindazole derivatives as potent PI3K/mTOR dual inhibitors based on our previously reported FD223. Among them, compound FD274 showed excellent dual PI3K/mTOR inhibitory activity, with IC50 values against PI3Kα/β/γ/δ and mTOR of 0.65 nM, 1.57 nM, 0.65 nM, 0.42 nM, and 2.03 nM, respectively, superior to compound FD223. Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC50 values of 0.092 μM and 0.084 μM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.
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Affiliation(s)
- Chengbin Yang
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China; Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, China
| | - Yi Chen
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China
| | - Tianze Wu
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China
| | - Yunjian Gao
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China
| | - Xiaofeng Liu
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China
| | - Yongtai Yang
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China
| | - Yun Ling
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China
| | - Yu Jia
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China
| | - Mingli Deng
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
| | - Jianxin Wang
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, China
| | - Yaming Zhou
- Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
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Gil D, Zarzycka M, Pabian J, Lekka M, Dulińska-Litewka J. Dual targeting of melanoma translation by MNK/eIF4E and PI3K/mTOR inhibitors. Cell Signal 2023:110742. [PMID: 37268164 DOI: 10.1016/j.cellsig.2023.110742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/24/2023] [Accepted: 05/28/2023] [Indexed: 06/04/2023]
Abstract
Melanoma is relatively resistant to chemotherapy, and no targeted therapies are fully effective. The most common mutations in melanoma result in hyperactivation of the mitogen-activated protein kinase (MAPK) and PI3K/AKT/ mTOR pathways responsible for initiating and controlling oncogenic protein translation. This makes both the signaling pathways potentially important therapeutic targets in melanoma. Our studies were carried out on human melanoma cell lines WM793 and 1205 LU with similar genomic alteration (BRAFV600E and PTEN loss). We used a highly specific PI3K/mTOR inhibitor, dactolisib (NVP-BEZ235), and Mnk inhibitor - CGP57380 alone and in combination. Here, we explore the mechanism of action of these drugs alone and in combination, as well as their effect on the viability and invasiveness of melanoma cells. Although when used independently, both drugs suppressed cell proliferation and migration, their combination has additional antitumor effects. We demonstrate that simultaneous inhibition of both pathways may prevent possible drug resistance.
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Affiliation(s)
- Dorota Gil
- Medical Biochemistry, Jagiellonian University Medical College, ul. Kopernika 7, 31-034 Kraków, Poland.
| | - Marta Zarzycka
- Medical Biochemistry, Jagiellonian University Medical College, ul. Kopernika 7, 31-034 Kraków, Poland
| | - Joanna Pabian
- Department of Biophysical Microstructures, Institute of Nuclear Physics Polish Academy of Sciences, PL-31342 Krakow, Poland
| | - Małgorzata Lekka
- Department of Biophysical Microstructures, Institute of Nuclear Physics Polish Academy of Sciences, PL-31342 Krakow, Poland
| | - Joanna Dulińska-Litewka
- Medical Biochemistry, Jagiellonian University Medical College, ul. Kopernika 7, 31-034 Kraków, Poland
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Aguayo F, Perez-Dominguez F, Osorio JC, Oliva C, Calaf GM. PI3K/AKT/mTOR Signaling Pathway in HPV-Driven Head and Neck Carcinogenesis: Therapeutic Implications. BIOLOGY 2023; 12:biology12050672. [PMID: 37237486 DOI: 10.3390/biology12050672] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023]
Abstract
High-risk human papillomaviruses (HR-HPVs) are the causal agents of cervical, anogenital and a subset of head and neck carcinomas (HNCs). Indeed, oropharyngeal cancers are a type of HNC highly associated with HR-HPV infections and constitute a specific clinical entity. The oncogenic mechanism of HR-HPV involves E6/E7 oncoprotein overexpression for promoting cell immortalization and transformation, through the downregulation of p53 and pRB tumor suppressor proteins, among other cellular targets. Additionally, E6/E7 proteins are involved in promoting PI3K/AKT/mTOR signaling pathway alterations. In this review, we address the relationship between HR-HPV and PI3K/AKT/mTOR signaling pathway activation in HNC with an emphasis on its therapeutic importance.
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Affiliation(s)
- Francisco Aguayo
- Departamento de Biomedicina, Facultad de Medicina, Universidad de Tarapacá, Arica 1000000, Chile
| | - Francisco Perez-Dominguez
- Laboratorio de Oncovirología, Programa de Virología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - Julio C Osorio
- Laboratorio de Oncovirología, Programa de Virología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - Carolina Oliva
- Laboratorio de Oncovirología, Programa de Virología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - Gloria M Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
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Ajay AK, Chu P, Patel P, Deban C, Roychowdhury C, Heda R, Halawi A, Saad A, Younis N, Zhang H, Jiang X, Nasr M, Hsiao LL, Lin G, Azzi JR. High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma. Pharmaceutics 2023; 15:1274. [PMID: 37111759 PMCID: PMC10145398 DOI: 10.3390/pharmaceutics15041274] [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: 02/06/2023] [Revised: 03/29/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
Chordomas account for approximately 1-4% of all malignant bone tumors and 20% of primary tumors of the spinal column. It is a rare disease, with an incidence estimated to be approximately 1 per 1,000,000 people. The underlying causative mechanism of chordoma is unknown, which makes it challenging to treat. Chordomas have been linked to the T-box transcription factor T (TBXT) gene located on chromosome 6. The TBXT gene encodes a protein transcription factor TBXT, or brachyury homolog. Currently, there is no approved targeted therapy for chordoma. Here, we performed a small molecule screening to identify small chemical molecules and therapeutic targets for treating chordoma. We screened 3730 unique compounds and selected 50 potential hits. The top three hits were Ribociclib, Ingenol-3-angelate, and Duvelisib. Among the top 10 hits, we found a novel class of small molecules, including proteasomal inhibitors, as promising molecules that reduce the proliferation of human chordoma cells. Furthermore, we discovered that proteasomal subunits PSMB5 and PSMB8 are increased in human chordoma cell lines U-CH1 and U-CH2, confirming that the proteasome may serve as a molecular target whose specific inhibition may lead to better therapeutic strategies for chordoma.
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Affiliation(s)
- Amrendra K. Ajay
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Philip Chu
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
| | - Poojan Patel
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Christa Deban
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
| | - Chitran Roychowdhury
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
| | - Radhika Heda
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
| | - Ahmad Halawi
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Anis Saad
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Nour Younis
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Hao Zhang
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Xiuju Jiang
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Mahmoud Nasr
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Li-Li Hsiao
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Gang Lin
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Jamil R. Azzi
- Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA (R.H.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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Ha S, Wang BD. Molecular Insight into Drug Resistance Mechanism Conferred by Aberrant PIK3CD Splice Variant in African American Prostate Cancer. Cancers (Basel) 2023; 15:1337. [PMID: 36831678 PMCID: PMC9954641 DOI: 10.3390/cancers15041337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/14/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023] Open
Abstract
Targeting PI3Kδ has emerged as a promising therapy for hematologic and non-hematologic malignancies. Previously, we identified an oncogenic splice variant, PIK3CD-S, conferring Idelalisib resistance in African American (AA) prostate cancer (PCa). In the current study, we employed a comprehensive analysis combining molecular biology, biochemistry, histology, in silico simulation, and in vitro functional assays to investigate the PIK3CD-S expression profiles in PCa samples and to elucidate the drug resistance mechanism mediated by PI3Kδ-S (encoded by PIK3CD-S). The immunohistochemistry, RT-PCR, and Western blot assays first confirmed that PI3Kδ-S is highly expressed in AA PCa. Compared with PCa expressing the full-length PI3Kδ-L, PCa expressing PI3Kδ-S exhibits enhanced drug resistance properties, including a higher cell viability, more antiapoptotic and invasive capacities, and constitutively activated PI3K/AKT signaling, in the presence of PI3Kδ/PI3K inhibitors (Idelalisib, Seletalisib, Wortmannin, and Dactolisib). Molecular docking, ATP-competitive assays, and PI3 kinase assays have further indicated a drastically reduced affinity of PI3Kδ inhibitors with PI3Kδ-S vs. PI3Kδ-L, attributed to the lack of core binding residues in the PI3Kδ-S catalytic domain. Additionally, SRSF2 has been identified as a critical splicing factor mediating exon 20 skipping in PIK3CD pre-mRNA. The inhibition of the SRSF2 activity by SRPIN340 successfully sensitizes AA PCa cells to PI3Kδ inhibitors, suggesting a novel therapeutic option for Idelalisib-resistant tumors.
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Affiliation(s)
- Siyoung Ha
- Department of Pharmaceutical Sciences, University of Maryland Eastern Shore School of Pharmacy and Health Professions, Princess Anne, MD 21853, USA
| | - Bi-Dar Wang
- Department of Pharmaceutical Sciences, University of Maryland Eastern Shore School of Pharmacy and Health Professions, Princess Anne, MD 21853, USA
- Hormone Related Cancers Program, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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Lv KH, Chen L, Zhao KH, Yang JM, Yan SJ. Cu-Catalyzed Decarboxylative Annulation of N-Phenylglycines with Maleimides: Synthesis of 1 H-Pyrrolo[3,4- c]quinoline-1,3(2 H)-diones. J Org Chem 2023; 88:2358-2366. [PMID: 36753732 DOI: 10.1021/acs.joc.2c02757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
A novel protocol for the construction of functionalized 1H-pyrrolo[3,4-c]quinoline-1,3(2H)-diones (PQLs, 3) from N-phenylglycines and maleimides was developed. The cascade reaction was enabled by heating a mixture of the two substrates in the presence of di-tert-butyl peroxide (DTBP) as an oxidant and anhydrous CuBr as a catalyst in chlorobenzene. Consequently, a diverse series of PQLs 3 were synthesized in moderate-to-good yields (43-73%). The synthesis of the PQLs was enabled via a one-pot cascade reaction that proceeded through subsequent oxidative decarboxylation, 1,2-addition, intramolecular cyclization, tautomerization, and aromatization reactions. This protocol can be used for the synthesis of functionalized PQLs via a one-pot oxidative decarboxylation annulation reaction rather than through a series of multistep reactions, making it suitable for both combinatorial and parallel syntheses of PQLs.
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Affiliation(s)
- Kai-Hong Lv
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, P. R. China
| | - Li Chen
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, P. R. China
| | - Ke-Hua Zhao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, P. R. China
| | - Jia-Ming Yang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, P. R. China
| | - Sheng-Jiao Yan
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, P. R. China
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Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS. Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario. Pharmaceutics 2023; 15:pharmaceutics15020664. [PMID: 36839989 PMCID: PMC9966033 DOI: 10.3390/pharmaceutics15020664] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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Affiliation(s)
- Marina Ferreira Candido
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Mariana Medeiros
- Regional Blood Center, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Luciana Chain Veronez
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - David Bastos
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Karla Laissa Oliveira
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Julia Alejandra Pezuk
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - María Sol Brassesco
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
- Correspondence: ; Tel.: +55-16-3315-9144; Fax: +55-16-3315-4886
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Occhiuzzi MA, Lico G, Ioele G, De Luca M, Garofalo A, Grande F. Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents. Eur J Med Chem 2023; 246:114971. [PMID: 36462440 DOI: 10.1016/j.ejmech.2022.114971] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022]
Abstract
The biochemical role of the PI3K/PKB/mTOR signalling pathway in cell-cycle regulation is now well known. During the onset and development of different forms of cancer it becomes overactive reducing apoptosis and allowing cell proliferation. Therefore, this pathway has become an important target for the treatment of various forms of malignant tumors, including breast cancer and follicular lymphoma. Recently, several more or less selective inhibitors targeting these proteins have been identified. In general, drugs that act on multiple targets within the entire pathway are more efficient than single targeting inhibitors. Multiple inhibitors exhibit high potency and limited drug resistance, resulting in promising anticancer agents. In this context, the present survey focuses on small molecule drugs capable of modulating the PI3K/PKB/mTOR signalling pathway, thus representing drugs or drug candidates to be used in the pharmacological treatment of different forms of cancer.
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Affiliation(s)
| | - Gernando Lico
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Giuseppina Ioele
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Michele De Luca
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Antonio Garofalo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Fedora Grande
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
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Huang J, Chen L, Wu J, Ai D, Zhang JQ, Chen TG, Wang L. Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions. J Med Chem 2022; 65:16033-16061. [PMID: 36503229 DOI: 10.1021/acs.jmedchem.2c01070] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.
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Affiliation(s)
- Jindi Huang
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Liye Chen
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Jiangxia Wu
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Daiqiao Ai
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Ji-Quan Zhang
- College of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Tie-Gen Chen
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Room 109, Building C, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan Tsuihang New District, Zhongshan, Guangdong 528400, China
| | - Ling Wang
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
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40
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Llaurado Fernandez M, Hijmans EM, Gennissen AM, Wong NK, Li S, Wisman GBA, Hamilton A, Hoenisch J, Dawson A, Lee CH, Bittner M, Kim H, DiMattia GE, Lok CA, Lieftink C, Beijersbergen RL, de Jong S, Carey MS, Bernards R, Berns K. NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition. Mol Cancer Ther 2022; 21:1862-1874. [PMID: 36198031 PMCID: PMC9716250 DOI: 10.1158/1535-7163.mct-22-0004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 05/30/2022] [Accepted: 10/03/2022] [Indexed: 01/12/2023]
Abstract
Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian cancer with high fatality rates in advanced stages due to its chemoresistant properties. LGSOC is characterized by activation of MAPK signaling, and recent clinical trials indicate that the MEK inhibitor (MEKi) trametinib may be a good treatment option for a subset of patients. Understanding MEKi-resistance mechanisms and subsequent identification of rational drug combinations to suppress resistance may greatly improve LGSOC treatment strategies. Both gain-of-function and loss-of-function CRISPR-Cas9 genome-wide libraries were used to screen LGSOC cell lines to identify genes that modulate the response to MEKi. Overexpression of MAML2 and loss of MAP3K1 were identified, both leading to overexpression of the NOTCH target HES1, which has a causal role in this process as its knockdown reversed MEKi resistance. Interestingly, increased HES1 expression was also observed in selected spontaneous trametinib-resistant clones, next to activating MAP2K1 (MEK1) mutations. Subsequent trametinib synthetic lethality screens identified SHOC2 downregulation as being synthetic lethal with MEKis. Targeting SHOC2 with pan-RAF inhibitors (pan-RAFis) in combination with MEKi was effective in parental LGSOC cell lines, in MEKi-resistant derivatives, in primary ascites cultures from patients with LGSOC, and in LGSOC (cell line-derived and patient-derived) xenograft mouse models. We found that the combination of pan-RAFi with MEKi downregulated HES1 levels in trametinib-resistant cells, providing an explanation for the synergy that was observed. Combining MEKis with pan-RAFis may provide a promising treatment strategy for patients with LGSOC, which warrants further clinical validation.
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Affiliation(s)
- Marta Llaurado Fernandez
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada
| | - E. Marielle Hijmans
- Division of Molecular Carcinogenesis, Oncode Institute, Cancer Genomics Center Netherlands, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Annemiek M.C. Gennissen
- Division of Molecular Carcinogenesis, Oncode Institute, Cancer Genomics Center Netherlands, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Nelson K.Y. Wong
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada.,Department of Experimental Therapeutics, BC Cancer, Vancouver, British Columbia, Canada
| | - Shang Li
- Department of Medical Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - G. Bea A. Wisman
- Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Aleksandra Hamilton
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada
| | - Joshua Hoenisch
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada
| | - Amy Dawson
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada
| | - Cheng-Han Lee
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada
| | - Madison Bittner
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada
| | - Hannah Kim
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada
| | - Gabriel E. DiMattia
- Mary and John Knight Translational Ovarian Cancer Research Unit, London Health Sciences Center
| | - Christianne A.R. Lok
- Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Cor Lieftink
- Division of Molecular Carcinogenesis, Oncode Institute, Cancer Genomics Center Netherlands, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Roderick L. Beijersbergen
- Division of Molecular Carcinogenesis, Oncode Institute, Cancer Genomics Center Netherlands, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Steven de Jong
- Department of Medical Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Mark S. Carey
- Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada.,Corresponding Authors: Katrien Berns, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-20-5121955. E-mail: ; and Mark S. Carey, Vancouver, British Columbia V6Z 2K8, Canada. Phone: 160-4875-4268; E-mail: ; René Bernards, Plesmanlaan 121,1066 CX Amsterdam, the Netherlands. Phone: 31-20-5121952; E-mail:
| | - René Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, Cancer Genomics Center Netherlands, the Netherlands Cancer Institute, Amsterdam, the Netherlands.,Corresponding Authors: Katrien Berns, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-20-5121955. E-mail: ; and Mark S. Carey, Vancouver, British Columbia V6Z 2K8, Canada. Phone: 160-4875-4268; E-mail: ; René Bernards, Plesmanlaan 121,1066 CX Amsterdam, the Netherlands. Phone: 31-20-5121952; E-mail:
| | - Katrien Berns
- Division of Molecular Carcinogenesis, Oncode Institute, Cancer Genomics Center Netherlands, the Netherlands Cancer Institute, Amsterdam, the Netherlands.,Corresponding Authors: Katrien Berns, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-20-5121955. E-mail: ; and Mark S. Carey, Vancouver, British Columbia V6Z 2K8, Canada. Phone: 160-4875-4268; E-mail: ; René Bernards, Plesmanlaan 121,1066 CX Amsterdam, the Netherlands. Phone: 31-20-5121952; E-mail:
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Colombo M, Passarelli F, Corsetto PA, Rizzo AM, Marabese M, De Simone G, Pastorelli R, Broggini M, Brunelli L, Caiola E. NSCLC Cells Resistance to PI3K/mTOR Inhibitors Is Mediated by Delta-6 Fatty Acid Desaturase (FADS2). Cells 2022; 11:cells11233719. [PMID: 36496978 PMCID: PMC9736998 DOI: 10.3390/cells11233719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/18/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway is one of the most common events in human cancers. Several efforts have been made toward the identification of selective PI3K pathway inhibitors. However, the success of these molecules has been partially limited due to unexpected toxicities, the selection of potentially responsive patients, and intrinsic resistance to treatments. Metabolic alterations are intimately linked to drug resistance; altered metabolic pathways can help cancer cells adapt to continuous drug exposure and develop resistant phenotypes. Here we report the metabolic alterations underlying the non-small cell lung cancer (NSCLC) cell lines resistant to the usual PI3K-mTOR inhibitor BEZ235. In this study, we identified that an increased unsaturation degree of lipid species is associated with increased plasma membrane fluidity in cells with the resistant phenotype and that fatty acid desaturase FADS2 mediates the acquisition of chemoresistance. Therefore, new studies focused on reversing drug resistance based on membrane lipid modifications should consider the contribution of desaturase activity.
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Affiliation(s)
- Marika Colombo
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Federico Passarelli
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Paola A. Corsetto
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Angela M. Rizzo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Mirko Marabese
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Giulia De Simone
- Protein and Metabolite Biomarkers Unit, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Roberta Pastorelli
- Protein and Metabolite Biomarkers Unit, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Massimo Broggini
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
- Correspondence: (M.B.); (L.B.)
| | - Laura Brunelli
- Protein and Metabolite Biomarkers Unit, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
- Correspondence: (M.B.); (L.B.)
| | - Elisa Caiola
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
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Leoncin M, La Starza R, Roti G, Pagliaro L, Bassan R, Mecucci C. Modern treatment approaches to adult acute T-lymphoblastic and myeloid/T-lymphoblastic leukemia: from current standards to precision medicine. Curr Opin Oncol 2022; 34:738-747. [PMID: 36017547 DOI: 10.1097/cco.0000000000000900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW To review the most recent advancements in the management of adult T-cell acute lymphoblastic leukemia (T-ALL), we summarize insights into molecular diagnostics, immunotherapy, targeted therapy and new techniques of drug sensitivity profiling that may support further therapeutic progress in T-ALL subsets. RECENT FINDINGS With current induction/consolidation chemotherapy and/or risk-oriented allogeneic stem cell transplantation programs up to 95% adult T-ALL patients achieve a remission and >50% (up to 80% in adolescents and young adults) are cured. The group of patients who fail upfront therapy, between 25% and 40%, is enriched in high-risk characteristics (unfavorable genetics, persistent minimal residual disease) and represents the ideal setting for the study of molecular mechanisms of disease resistance, and consequently explore novel ways of restoration of drug sensitivity and assess patient/subset-specific patterns of drug vulnerability to targeting agents, immunotherapy and cell therapy. SUMMARY The emerging evidence supports the contention that precision medicine may soon allow valuable therapeutic chances to adult patients with high-risk T-ALL. The ongoing challenge is to identify the best way to integrate all these new data into the therapeutic path of newly diagnosed patients, with a view to optimize the individual treatment plan and increase the cure rate.
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Affiliation(s)
- Matteo Leoncin
- Hematology Unit, Azienda Ulss3 Serenissima, Ospedale dell'Angelo, Venezia-Mestre
| | | | - Giovanni Roti
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Luca Pagliaro
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Renato Bassan
- Hematology Unit, Azienda Ulss3 Serenissima, Ospedale dell'Angelo, Venezia-Mestre
| | - Cristina Mecucci
- Department of Medicine and Surgery, University of Perugia, Perugia
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Yang J, Liu Y, Lan S, Yu S, Ma X, Luo D, Shan H, Zhong X, Yan G, Li R. Discovery of 2-Methyl-2-(4-(2-methyl-8-(1 H-pyrrolo[2,3- b]pyridin-6-yl)-1 H-naphtho[1,2- d]imidazol-1-yl)phenyl)propanenitrile as a Novel PI3K/mTOR Inhibitor with Enhanced Antitumor Efficacy In Vitro and In Vivo. J Med Chem 2022; 65:12781-12801. [PMID: 36191148 DOI: 10.1021/acs.jmedchem.2c00572] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
PI3K/Akt/mTOR signaling pathway is a validated drug target for cancer treatment that plays a critical role in controlling tumor growth, proliferation, and apoptosis. However, no FDA-approved PI3K/mTOR dual inhibitor exists. Thus, a candidate with a better curative effect and lower toxicity is still urgently needed. Herein, we design, synthesize, and evaluate compounds belonging to a novel series of 2-methyl-1H-imidazo[4,5-c]quinoline scaffold derivatives as PI3K/mTOR dual inhibitors. Among them, compound 8o was identified as a novel candidate with excellent kinase selectivity. It manifested remarkable antiproliferative activities against SW620 and HeLa cells. Western blot and immunohistochemical analysis results proved that 8o could regulate the PI3K/AKT/mTOR signaling pathway by inhibiting the phosphorylation of AKT and S6 proteins. Additionally, 8o presented a favorable pharmacokinetic property (oral bioavailability of 76.8%) and significant antitumor efficacy in vivo without obvious toxicity. Collectively, these results indicated that 8o is a promising agent for cancer treatment and merits further development.
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Affiliation(s)
- Jie Yang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.,Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China.,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Yuanyuan Liu
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Suke Lan
- College of Chemistry & Environment Protection Engineering, Southwest Minzu University, Chengdu 610041, China
| | - Su Yu
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Xinyu Ma
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Dan Luo
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Huifang Shan
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Xinxin Zhong
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Guoyi Yan
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Rui Li
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
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Zhao K, Li Y, Qiu Y, Huang R, Lin M, Chen L, Liu Y. Norkurarinone and isoxanthohumol inhibit high glucose and hypoxia-induced angiogenesis via improving oxidative stress and regulating autophagy in human retinal microvascular endothelial cells. Biochem Biophys Res Commun 2022; 634:20-29. [DOI: 10.1016/j.bbrc.2022.09.095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 09/22/2022] [Accepted: 09/24/2022] [Indexed: 11/02/2022]
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45
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Chan Wah Hak CML, Rullan A, Patin EC, Pedersen M, Melcher AA, Harrington KJ. Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy. Front Oncol 2022; 12:971959. [PMID: 36106115 PMCID: PMC9465159 DOI: 10.3389/fonc.2022.971959] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Radiotherapy is one of the most effective and frequently used treatments for a wide range of cancers. In addition to its direct anti-cancer cytotoxic effects, ionising radiation can augment the anti-tumour immune response by triggering pro-inflammatory signals, DNA damage-induced immunogenic cell death and innate immune activation. Anti-tumour innate immunity can result from recruitment and stimulation of dendritic cells (DCs) which leads to tumour-specific adaptive T-cell priming and immunostimulatory cell infiltration. Conversely, radiotherapy can also induce immunosuppressive and anti-inflammatory mediators that can confer radioresistance. Targeting the DNA damage response (DDR) concomitantly with radiotherapy is an attractive strategy for overcoming radioresistance, both by enhancing the radiosensitivity of tumour relative to normal tissues, and tipping the scales in favour of an immunostimulatory tumour microenvironment. This two-pronged approach exploits genomic instability to circumvent immune evasion, targeting both hallmarks of cancer. In this review, we describe targetable DDR proteins (PARP (poly[ADP-ribose] polymerase); ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) and Wee1 (Wee1-like protein kinase) and their potential intersections with druggable immunomodulatory signalling pathways, including nucleic acid-sensing mechanisms (Toll-like receptors (TLR); cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and retinoic acid-inducible gene-I (RIG-I)-like receptors), and how these might be exploited to enhance radiation therapy. We summarise current preclinical advances, recent and ongoing clinical trials and the challenges of therapeutic combinations with existing treatments such as immune checkpoint inhibitors.
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Affiliation(s)
| | - Antonio Rullan
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Emmanuel C. Patin
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Malin Pedersen
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Alan A. Melcher
- Translational Immunotherapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Kevin J. Harrington
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
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46
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Danielpour D, Corum S, Leahy P, Bangalore A. Jagged-1 is induced by mTOR inhibitors in renal cancer cells through an Akt/ALK5/Smad4-dependent mechanism. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100117. [PMID: 35992379 PMCID: PMC9389240 DOI: 10.1016/j.crphar.2022.100117] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 06/20/2022] [Accepted: 06/30/2022] [Indexed: 11/16/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) plays an important role in the aggressiveness and therapeutic resistance of many cancers. Targeting mTOR continues to be under clinical investigation for cancer therapy. Despite the notable clinical success of mTOR inhibitors in extending the overall survival of patients with certain malignancies including metastatic renal cell carcinomas (RCCs), the overall impact of mTOR inhibitors on cancers has been generally disappointing and attributed to various compensatory responses. Here we provide the first report that expression of the Notch ligand Jagged-1 (JAG1), which is associated with aggressiveness of RCCs, is induced by several inhibitors of mTOR (rapamycin (Rap), BEZ235, KU-0063794) in human clear cell RCC (ccRCC) cells. Using both molecular and chemical inhibitors of PI3K, Akt, and TGF-β signaling, we provide evidence that the induction of JAG1 expression by mTOR inhibitors in ccRCC cells depends on the activation of Akt and occurs through an ALK5 kinase/Smad4-dependent mechanism. Furthermore, we show that mTOR inhibitors activate Notch1 and induce the expression of drivers of epithelial-mesenchymal transition, notably Hic-5 and Slug. Silencing JAG1 with selective shRNAs blocked the ability of KU-0063794 and Rap to induce Hic-5 in ccRCC cells. Moreover, Rap enhanced TGF-β-induced expression of Hic-5 and Slug, both of which were repressed in JAG1-silenced ccRCC cells. Silencing JAG1 selectively decreased the motility of ccRCC cells treated with Rap or TGF-β1. Moreover, inhibition of Notch signaling with γ-secretase inhibitors enhanced or permitted mTOR inhibitors to suppress the motility of ccRCC cells. We suggest targeting JAG1 may enhance therapeutic responses to mTOR inhibitors in ccRCCs.
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Key Words
- ALK5, Activin-like kinase 5 (TGF-β type I receptor)
- ANOVA, Analysis of variance
- Akt
- BEZ235
- BSA, Bovine serum albumin
- EDTA, Ethylenediaminetetraacetic acid
- EMT
- FBS, Fetal bovine serum
- Hic-5
- Hic-5, Hydrogen peroxide-inducible clone 5, also known as transforming growth factor beta induced transcript
- IRS-1, Insulin receptor substrate-1
- JAG1, Jagged-1
- KU-0063794
- MAML-1, Mastermind-like protein-1
- Myr, Myristoylated
- PI3K
- PI3K, Phosphatidylinositol 3-kinase
- RCC, RCC
- Rap, Rapamycin
- Rapamycin
- Renal cancer
- Rheb, Ras homologue enriched in brain
- SE, Standard error
- Slug
- Slug, Snail family of transcription factors encoded by the SNAI2 gene
- Smad, Mothers against decapentaplegic homolog
- Smad4
- TGF-beta
- TGF-β, Transforming growth factor-beta
- TSC, Tuberous Sclerosis Complex
- TβRI, Transforming growth factor β receptor type 1
- TβRII, Transforming growth factor β receptor type 2
- ccRCC, Clear cell renal cell carcinoma
- mRCC, Metastatic renal cell carcinoma
- mTOR
- mTORC1, Mammalian target of rapamycin complex 1
- mTORC2, Mammalian target of rapamycin complex 2
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Affiliation(s)
- David Danielpour
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Pharmacology Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Urology University Hospitals of Cleveland, Cleveland, OH, 44106, USA
| | - Sarah Corum
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Patrick Leahy
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Anusha Bangalore
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology Case Western Reserve University, Cleveland, OH, 44106, USA
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Subtil FSB, Gröbner C, Recknagel N, Parplys AC, Kohl S, Arenz A, Eberle F, Dikomey E, Engenhart-Cabillic R, Schötz U. Dual PI3K/mTOR Inhibitor NVP-BEZ235 Leads to a Synergistic Enhancement of Cisplatin and Radiation in Both HPV-Negative and -Positive HNSCC Cell Lines. Cancers (Basel) 2022; 14:cancers14133160. [PMID: 35804930 PMCID: PMC9265133 DOI: 10.3390/cancers14133160] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Head and neck cancers (HNSCCs), especially in the advanced stages, are predominantly treated by radiochemotherapy, including cisplatin. The cure rates are clearly higher for HPV-positive HNSCCs when compared to HPV-negative HNSCCs. For both entities, this treatment is accompanied by serious adverse reactions, mainly due to cisplatin administration. We reported earlier that for both HPV-positive and negative HNSCC cells, the effect of radiotherapy was strongly enhanced when pretreated using the dual PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235). The current study shows that for HPV-positive cells, BEZ235 will strongly enhance the effect of cisplatin alone. More important, preincubation with BEZ235 was found to alter the purely additive effect normally seen when cisplatin is combined with radiation into a strong synergistic enhancement. This tri-modal combination might allow for the enhancement of the effect of radiochemotherapy, even with reduced cisplatin. Abstract The standard of care for advanced head and neck cancers (HNSCCs) is radiochemotherapy, including cisplatin. This treatment results in a cure rate of approximately 85% for oropharyngeal HPV-positive HNSCCs, in contrast to only 50% for HPV-negative HNSCCs, and is accompanied by severe side effects for both entities. Therefore, innovative treatment modalities are required, resulting in a better outcome for HPV-negative HNSCCs, and lowering the adverse effects for both entities. The effect of the dual PI3K/mTOR inhibitor NVP-BEZ235 on a combined treatment with cisplatin and radiation was studied in six HPV-negative and six HPV-positive HNSCC cell lines. Cisplatin alone was slightly more effective in HPV-positive cells. This could be attributed to a defect in homologous recombination, as demonstrated by depleting RAD51. Solely for HPV-positive cells, pretreatment with BEZ235 resulted in enhanced cisplatin sensitivity. For the combination of cisplatin and radiation, additive effects were observed. However, when pretreated with BEZ235, this combination changed into a synergistic interaction, with a slightly stronger enhancement for HPV-positive cells. This increase could be attributed to a diminished degree of DSB repair in G1, as visualized via the detection of γH2AX/53BP1 foci. BEZ235 can be used to enhance the effect of combined treatment with cisplatin and radiation in both HPV-negative and -positive HNSCCs.
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Affiliation(s)
- Florentine S. B. Subtil
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Carolin Gröbner
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Niklas Recknagel
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Ann Christin Parplys
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Sibylla Kohl
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Andrea Arenz
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Fabian Eberle
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Ekkehard Dikomey
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Rita Engenhart-Cabillic
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Ulrike Schötz
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
- Correspondence: ; Tel.: +49-6421-28-21978
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Abstract
The mechanistic target of the rapamycin (mTOR) signaling pathway is the central regulator of cell growth and proliferation by integrating growth factor and nutrient availability. Under healthy physiological conditions, this process is tightly coordinated and essential to maintain whole-body homeostasis. Not surprisingly, dysregulated mTOR signaling underpins several diseases with increasing incidence worldwide, including obesity, diabetes, and cancer. Consequently, there is significant clinical interest in developing therapeutic strategies that effectively target this pathway. The transition of mTOR inhibitors from the bench to bedside, however, has largely been marked with challenges and shortcomings, such as the development of therapy resistance and adverse side effects in patients. In this review, we discuss the current status of first-, second-, and third-generation mTOR inhibitors as a cancer therapy in both preclinical and clinical settings, with a particular emphasis on the mechanisms of drug resistance. We focus especially on the emerging role of diet as an important environmental determinant of therapy response, and posit a conceptual framework that links nutrient availability and whole-body metabolic states such as obesity with many of the previously defined processes that drive resistance to mTOR-targeted therapies. Given the role of mTOR as a central integrator of cell metabolism and function, we propose that modulating nutrient inputs through dietary interventions may influence the signaling dynamics of this pathway and compensatory nodes. In doing so, new opportunities for exploiting diet/drug synergies are highlighted that may unlock the therapeutic potential of mTOR inhibitors as a cancer treatment.
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Affiliation(s)
- Nikos Koundouros
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021,USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
- Correspondence: Nikos Koundouros, Meyer Cancer Center, Weill Cornell Medicine, 413 East 69th Street, New York, NY, 10021 USA.
| | - John Blenis
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021,USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
- Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA
- Correspondence: John Blenis, Meyer Cancer Center, Weill Cornell Medicine, 413 East 69th Street, New York, NY, 10021 USA.
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49
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Xu Z, Chu M. Advances in Immunosuppressive Agents Based on Signal Pathway. Front Pharmacol 2022; 13:917162. [PMID: 35694243 PMCID: PMC9178660 DOI: 10.3389/fphar.2022.917162] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/02/2022] [Indexed: 12/13/2022] Open
Abstract
Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.
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Affiliation(s)
- Zhiqing Xu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Pharmacology, Jilin University, Changchun, China
| | - Ming Chu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
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50
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Fairhurst RA, Furet P, Imbach-Weese P, Stauffer F, Rueeger H, McCarthy C, Ripoche S, Oswald S, Arnaud B, Jary A, Maira M, Schnell C, Guthy DA, Wartmann M, Kiffe M, Desrayaud S, Blasco F, Widmer T, Seiler F, Gutmann S, Knapp M, Caravatti G. Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor. J Med Chem 2022; 65:8345-8379. [PMID: 35500094 DOI: 10.1021/acs.jmedchem.2c00267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor 40 (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of 40 in a clinical study is discussed.
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Affiliation(s)
- Robin A Fairhurst
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Pascal Furet
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | | | - Frédéric Stauffer
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Heinrich Rueeger
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Clive McCarthy
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Sebastien Ripoche
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Susanne Oswald
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Bertrand Arnaud
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Aline Jary
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Michel Maira
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Christian Schnell
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Daniel A Guthy
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Markus Wartmann
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Michael Kiffe
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | | | - Francesca Blasco
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Toni Widmer
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Frank Seiler
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Sascha Gutmann
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Mark Knapp
- Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States
| | - Giorgio Caravatti
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
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