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Tang Y, Fan Y. Combined KRAS and TP53 mutation in patients with colorectal cancer enhance chemoresistance to promote postoperative recurrence and metastasis. BMC Cancer 2024; 24:1155. [PMID: 39289671 PMCID: PMC11409552 DOI: 10.1186/s12885-024-12776-8] [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: 05/26/2024] [Accepted: 08/06/2024] [Indexed: 09/19/2024] Open
Abstract
The response of patients with colorectal cancer to chemotherapy is tightly correlated with their genomic variation. Among these, APC, TP53, KRAS, PIK3CA are the most frequently mutated genes in advanced colorectal cancer patients. However, the precise correlation between these mutations and the therapeutic effects of chemotherapy remains elusive. Here, we conducted genome sequencing to identify commonly mutated genes in colorectal cancer patients and comprehensively assessed their sensitivity to chemotherapy drugs by monitoring computer tomography (CT) scans and carcinoembryonic antigen (CEA) levels. Surprisingly, we discovered that the objective response rate to the standard first-line chemotherapy among patients harboring combined KRAS and TP53 mutations is dismal, and these patients are predisposed to recurrence and metastasis. Furthermore, advanced-stage patients with concurrent KRAS and TP53 mutations are susceptible to developing cancer-associated cachexia due to chemotherapy resistance or forced cessation of treatment. Our findings underscore the urgent need for the development of innovative and novel chemotherapeutic strategies to effectively manage colorectal cancer patients harboring combined KRAS and TP53 mutations.
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Affiliation(s)
- YiMeng Tang
- Department of General Surgery, The Third Hospital of MianYang, Sichuan Mental Health Center, MianYang, 621000, China
| | - Yao Fan
- Department of General Surgery, The Third Hospital of MianYang, Sichuan Mental Health Center, MianYang, 621000, China.
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Alsharoh H, Chiroi P, Isachesku E, Tanasa RA, Pop OL, Pirlog R, Berindan-Neagoe I. Personalizing Therapy Outcomes through Mitogen-Activated Protein Kinase Pathway Inhibition in Non-Small Cell Lung Cancer. Biomedicines 2024; 12:1489. [PMID: 39062063 PMCID: PMC11275062 DOI: 10.3390/biomedicines12071489] [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: 04/29/2024] [Revised: 06/18/2024] [Accepted: 07/02/2024] [Indexed: 07/28/2024] Open
Abstract
Lung cancer (LC) is a highly invasive malignancy and the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) as its most prevalent histological subtype. Despite all breakthroughs achieved in drug development, the prognosis of NSCLC remains poor. The mitogen-activated protein kinase signaling cascade (MAPKC) is a complex network of interacting molecules that can drive oncogenesis, cancer progression, and drug resistance when dysregulated. Over the past decades, MAPKC components have been used to design MAPKC inhibitors (MAPKCIs), which have shown varying efficacy in treating NSCLC. Thus, recent studies support the potential clinical use of MAPKCIs, especially in combination with other therapeutic approaches. This article provides an overview of the MAPKC and its inhibitors in the clinical management of NSCLC. It addresses the gaps in the current literature on different combinations of selective inhibitors while suggesting two particular therapy approaches to be researched in NSCLC: parallel and aggregate targeting of the MAPKC. This work also provides suggestions that could serve as a potential guideline to aid future research in MAPKCIs to optimize clinical outcomes in NSCLC.
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Affiliation(s)
- Hasan Alsharoh
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (H.A.); (P.C.); (E.I.); (I.B.-N.)
| | - Paul Chiroi
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (H.A.); (P.C.); (E.I.); (I.B.-N.)
| | - Ekaterina Isachesku
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (H.A.); (P.C.); (E.I.); (I.B.-N.)
| | | | - Ovidiu-Laurean Pop
- Department of Morphology Sciences, University of Oradea, 410087 Oradea, Romania;
| | - Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (H.A.); (P.C.); (E.I.); (I.B.-N.)
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (H.A.); (P.C.); (E.I.); (I.B.-N.)
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3
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Wang W, Albadari N, Du Y, Fowler JF, Sang HT, Xian W, McKeon F, Li W, Zhou J, Zhang R. MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future. Pharmacol Rev 2024; 76:414-453. [PMID: 38697854 PMCID: PMC11068841 DOI: 10.1124/pharmrev.123.001026] [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: 08/22/2023] [Revised: 11/28/2023] [Accepted: 01/16/2024] [Indexed: 05/05/2024] Open
Abstract
Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.
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Affiliation(s)
- Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Najah Albadari
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Yi Du
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Josef F Fowler
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Hannah T Sang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Wa Xian
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Frank McKeon
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Wei Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Jia Zhou
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
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Alaseem AM. Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens. Saudi Pharm J 2023; 31:101790. [PMID: 37818252 PMCID: PMC10561124 DOI: 10.1016/j.jsps.2023.101790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/12/2023] [Indexed: 10/12/2023] Open
Abstract
Cancer cells often depend on multiple pathways for their growth and survival, resulting in therapeutic resistance and the limited effectiveness of treatments. Combination therapy has emerged as a favorable approach to enhance treatment efficacy and minimize acquired resistance and harmful side effects. The murine double minute 2 (MDM2) protein regulates cellular proliferation and promotes cancer-related activities by negatively regulating the tumor suppressor protein p53. MDM2 aberrations have been reported in a variety of human cancers, making it an appealing target for cancer therapy. As a result, several small-molecule MDM2 inhibitors have been developed and are currently being investigated in clinical studies. Nevertheless, it has been shown that the inhibition of MDM2 alone is inadequate to achieve long-term suppression of tumor growth, thus prompting the need for further investigation into combination therapeutic strategies. In this review, possible clinical and preclinical MDM2 combination inhibitor regimens are thoroughly analyzed and discussed. It provides a rationale for combining MDM2 inhibitors with other therapeutic approaches in the management of cancer, taking into consideration ongoing clinical trials that evaluate the combination of MDM2 inhibitors. The review explores the current status of MDM2 inhibitors in combination with chemotherapy or targeted therapy, as well as promising approach of combining MDM2 inhibitors with immunotherapy. In addition, it investigates the function of PROTACs as MDM2 degraders in cancer treatment. A comprehensive examination of these combination regimens highlights the potential for advancing MDM2-inhibitor therapy and improving clinical outcomes for cancer patients and establishes the foundation for future research and development in this promising area of study.
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Affiliation(s)
- Ali M. Alaseem
- Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
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5
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Tang YL, Li DD, Duan JY, Sheng LM, Wang X. Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments. World J Gastroenterol 2023; 29:926-948. [PMID: 36844139 PMCID: PMC9950860 DOI: 10.3748/wjg.v29.i6.926] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/24/2022] [Accepted: 01/31/2023] [Indexed: 02/10/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal and common malignancies in the world. Chemotherapy has been the conventional treatment for metastatic CRC (mCRC) patients. However, the effects of chemotherapy have been unsatisfactory. With the advent of targeted therapy, the survival of patients with CRC have been prolonged. Over the past 20 years, targeted therapy for CRC has achieved substantial progress. However, targeted therapy has the same challenge of drug resistance as chemotherapy. Consequently, exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy, along with searching for novel effective regimens, is a constant challenge in the mCRC treatment, and it is also a hot research topic. In this review, we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.
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Affiliation(s)
- Yuan-Ling Tang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dan-Dan Li
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yu Duan
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei-Ming Sheng
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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6
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Pairawan S, Akcakanat A, Kopetz S, Tapia C, Zheng X, Chen H, Ha MJ, Rizvi Y, Holla V, Wang J, Evans KW, Zhao M, Busaidy N, Fang B, Roth JA, Dumbrava EI, Meric-Bernstam F. Combined MEK/MDM2 inhibition demonstrates antitumor efficacy in TP53 wild-type thyroid and colorectal cancers with MAPK alterations. Sci Rep 2022; 12:1248. [PMID: 35075200 PMCID: PMC8786858 DOI: 10.1038/s41598-022-05193-z] [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: 07/12/2021] [Accepted: 12/14/2021] [Indexed: 11/08/2022] Open
Abstract
Most tumors with activating MAPK (mitogen-activated protein kinase) pathway alterations respond poorly to MEK inhibitors alone. Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in TP53 wild-type and MAPK altered colon and thyroid cancer models. In vitro, we showed synergy between selumetinib and KRT-232 on cell proliferation and colony formation assays. Immunoblotting confirmed p53 upregulation and MEK pathway inhibition. The combination was tested in vivo in seven patient-derived xenograft (PDX) models (five colorectal carcinoma and two papillary thyroid carcinoma models) with different KRAS, BRAF, and NRAS mutations. Combination therapy significantly prolonged event-free survival compared with monotherapy in six of seven models tested. Reverse-phase protein arrays and immunohistochemistry, respectively, demonstrated upregulation of the p53 pathway and in two models cleaved caspase 3 with combination therapy. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations.
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Affiliation(s)
- Seyed Pairawan
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Argun Akcakanat
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Coya Tapia
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Epizyme Inc., Boston, USA
| | - Xiaofeng Zheng
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Huiqin Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Min Jin Ha
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yasmeen Rizvi
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Vijaykumar Holla
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kurt W Evans
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ming Zhao
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Naifa Busaidy
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Bingliang Fang
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jack A Roth
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ecaterina Ileana Dumbrava
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, FC8.3044, Houston, TX, 77030, USA.
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Haronikova L, Bonczek O, Zatloukalova P, Kokas-Zavadil F, Kucerikova M, Coates PJ, Fahraeus R, Vojtesek B. Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them? Cell Mol Biol Lett 2021; 26:53. [PMID: 34911439 PMCID: PMC8903693 DOI: 10.1186/s11658-021-00293-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/05/2021] [Indexed: 12/13/2022] Open
Abstract
Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine.
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Affiliation(s)
- Lucia Haronikova
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
| | - Ondrej Bonczek
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
- Department of Medical Biosciences, Umea University, 901 87, Umea, Vasterbotten, Sweden
| | - Pavlina Zatloukalova
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
| | - Filip Kokas-Zavadil
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
| | - Martina Kucerikova
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
- National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
| | - Philip J Coates
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
| | - Robin Fahraeus
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
- Department of Medical Biosciences, Umea University, 901 87, Umea, Vasterbotten, Sweden
- Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010, Paris, France
| | - Borivoj Vojtesek
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
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Saleh MN, Patel MR, Bauer TM, Goel S, Falchook GS, Shapiro GI, Chung KY, Infante JR, Conry RM, Rabinowits G, Hong DS, Wang JS, Steidl U, Walensky LD, Naik G, Guerlavais V, Vukovic V, Annis DA, Aivado M, Meric-Bernstam F. Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type TP53. Clin Cancer Res 2021; 27:5236-5247. [PMID: 34301750 PMCID: PMC9401461 DOI: 10.1158/1078-0432.ccr-21-0715] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/16/2021] [Accepted: 07/21/2021] [Indexed: 01/07/2023]
Abstract
PURPOSE We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors. PATIENTS AND METHODS Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days. RESULTS Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg) and 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. CONCLUSIONS ALRN-6924 was well tolerated and demonstrated antitumor activity.
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Affiliation(s)
- Mansoor N. Saleh
- O'Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, Birmingham, Alabama.,Corresponding Authors: Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1226; E-mail: ; and Mansoor N. Saleh, Aga Khan University Nairobi, 3rd Parklands/Limuru Rd., Nairobi, Kenya. Phone: 254-709-93-1500; E-mail:
| | - Manish R. Patel
- Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida
| | - Todd M. Bauer
- Sarah Cannon Research Institute and Tennessee Oncology, Nashville, Tennessee
| | - Sanjay Goel
- Albert Einstein College of Medicine—Montefiore Medical Center, The Bronx, New York
| | | | | | - Ki Y. Chung
- Prisma Health Cancer Institute, Greenville, South Carolina
| | - Jeffrey R. Infante
- Sarah Cannon Research Institute and Tennessee Oncology, Nashville, Tennessee
| | | | | | - David S. Hong
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Judy S. Wang
- Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida
| | - Ulrich Steidl
- Albert Einstein College of Medicine—Montefiore Medical Center, The Bronx, New York
| | | | - Gurudatta Naik
- O'Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, Birmingham, Alabama
| | | | | | | | - Manuel Aivado
- Aileron Therapeutics, Inc., Watertown, Massachusetts
| | - Funda Meric-Bernstam
- The University of Texas MD Anderson Cancer Center, Houston, Texas.,Corresponding Authors: Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1226; E-mail: ; and Mansoor N. Saleh, Aga Khan University Nairobi, 3rd Parklands/Limuru Rd., Nairobi, Kenya. Phone: 254-709-93-1500; E-mail:
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9
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Patelli G, Tosi F, Amatu A, Mauri G, Curaba A, Patanè DA, Pani A, Scaglione F, Siena S, Sartore-Bianchi A. Strategies to tackle RAS-mutated metastatic colorectal cancer. ESMO Open 2021; 6:100156. [PMID: 34044286 PMCID: PMC8167159 DOI: 10.1016/j.esmoop.2021.100156] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/18/2022] Open
Abstract
The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRASG12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRASG12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRASG12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.
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Affiliation(s)
- G Patelli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - F Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - A Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - G Mauri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - A Curaba
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - D A Patanè
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - A Pani
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - F Scaglione
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Clinical Pharmacology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - S Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - A Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy.
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10
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Patwardhan GA, Marczyk M, Wali VB, Stern DF, Pusztai L, Hatzis C. Treatment scheduling effects on the evolution of drug resistance in heterogeneous cancer cell populations. NPJ Breast Cancer 2021; 7:60. [PMID: 34040000 PMCID: PMC8154902 DOI: 10.1038/s41523-021-00270-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
The effect of scheduling of targeted therapy combinations on drug resistance is underexplored in triple-negative breast cancer (TNBC). TNBC constitutes heterogeneous cancer cell populations the composition of which can change dynamically during treatment resulting in the selection of resistant clones with a fitness advantage. We evaluated crizotinib (ALK/MET inhibitor) and navitoclax (ABT-263; Bcl-2/Bcl-xL inhibitor) combinations in a large design consisting of 696 two-cycle sequential and concomitant treatment regimens with varying treatment dose, duration, and drug holiday length over a 26-day period in MDA-MB-231 TNBC cells and found that patterns of resistance depend on the schedule and sequence in which the drugs are given. Further, we tracked the clonal dynamics and mechanisms of resistance using DNA-integrated barcodes and single-cell RNA sequencing. Our study suggests that longer formats of treatment schedules in vitro screening assays are required to understand the effects of resistance and guide more realistically in vivo and clinical studies.
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Affiliation(s)
- Gauri A Patwardhan
- Breast Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA
| | - Michal Marczyk
- Breast Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA
- Department of Data Science and Engineering, Silesian University of Technology, Gliwice, Poland
| | - Vikram B Wali
- Breast Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA
| | - David F Stern
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Lajos Pusztai
- Breast Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA
| | - Christos Hatzis
- Breast Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
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11
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Wang X, Yamamoto Y, Imanishi M, Zhang X, Sato M, Sugaya A, Hirose M, Endo S, Natori Y, Moriwaki T, Yamato K, Hyodo I. Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild-type TP53 colon and gastric cancer cells with aberrant KRAS signaling. Oncol Lett 2021; 22:558. [PMID: 34084225 PMCID: PMC8161467 DOI: 10.3892/ol.2021.12819] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
Murine double minute homolog 2 (MDM2) is an oncoprotein that induces p53 degradation via ubiquitin-ligase activity. MDM4 cooperates with MDM2-mediated p53 degradation, directly inhibiting p53 transcription by binding to its transactivation domain. Our previous study reported that the simultaneous inhibition of MDM2 and MDM4 using nutlin-3 (an inhibitor of the MDM2-p53 interaction) and chimeric small interfering RNA with DNA-substituted seed arms (named chiMDM2 and chiMDM4) more potently activated p53 than the MDM2 or MDM4 inhibitor alone and synergistically augmented antitumor effects in various types of cancer cells with the wild-type (wt) TP53. Recently, the synergism of MDM2 and mitogen-activated protein kinase kinase (MEK) inhibitors has been demonstrated in wt TP53 colorectal and non-small cell lung cancer cells harboring mutant-type (mt) KRAS. The current study examined whether chiMDM4 augmented the synergistic antitumor effects of MDM2 and MEK inhibition using chiMDM2 or nutlin-3 and trametinib, respectively. ChiMDM2 and trametinib used in combination demonstrated a synergistic antitumor activity in HCT116 and LoVo colon cancer cells, and SNU-1 gastric cancer cells harboring wt TP53 and mt KRAS. Furthermore, chiMDM4 synergistically enhanced this combinational effect. Similar results were observed when nutlin-3 was used instead of chiMDM2. MDM4/MDM2 double knockdown combined with trametinib treatment enhanced G1 arrest and apoptosis induction. This was associated with the accumulation of p53, suppression of phosphorylated-extracellular signal-regulated kinase 2, inhibition of retinoblastoma phosphorylation, suppression of E2F1-activated proteins, and potent activation of pro-apoptotic proteins, such as Fas and p53 upregulated modulator of apoptosis. The results inidcated that the triple inhibition of MDM4, MDM2 and MEK exerted a potent antitumor effect in wt TP53 colon and gastric cancer cells with mt KRAS. Simultaneous activation of p53 and inhibition of aberrant KRAS signaling may be a rational treatment strategy for gastrointestinal tumors.
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Affiliation(s)
- Xiaoxuan Wang
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yoshiyuki Yamamoto
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Mamiko Imanishi
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Xiaochen Zhang
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Masashi Sato
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Akinori Sugaya
- Division of Gastroenterology, Ibaraki Prefectural Central Hospital, Kasama, Ibaraki 309-1793, Japan
| | - Mitsuaki Hirose
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.,Department of Gastroenterology, Tsuchiura Clinical Education and Training Center, University of Tsukuba Hospital, Tsuchiura, Ibaraki 300-8585, Japan
| | - Shinji Endo
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.,Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba 270-0034, Japan
| | | | - Toshikazu Moriwaki
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Kenji Yamato
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Ichinosuke Hyodo
- Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.,Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Ehime 791-0280, Japan
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12
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Ou M, Xu X, Chen Y, Li L, Zhang L, Liao Y, Sun W, Quach C, Feng J, Tang L. MDM2 induces EMT via the B‑Raf signaling pathway through 14‑3‑3. Oncol Rep 2021; 46:120. [PMID: 33955525 PMCID: PMC8129971 DOI: 10.3892/or.2021.8071] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 03/23/2021] [Indexed: 12/28/2022] Open
Abstract
MDM2 proto-oncogene, E3 ubiquitin protein ligase (MDM2) is a well-known oncogene and has been reported to be closely associated with epithelial-to-mesenchymal transition (EMT). The present study first demonstrated that the expression levels of MDM2 were markedly increased in TGF-β-induced EMT using quantitative PCR and western blotting. In addition, MDM2 was demonstrated to be associated with pathological grade in clinical glioma samples by immunohistochemical staining. Furthermore, overexpression of MDM2 promoted EMT in glioma, lung cancer and breast cancer cell lines using a scratch wound migration assay. Subsequently, the present study explored the mechanism by which MDM2 promoted EMT and revealed that MDM2 induced EMT by upregulating EMT-related transcription factors via activation of the B-Raf signaling pathway through tyrosine 3-monooxygenase activation protein ε using RNA sequencing and western blotting. This mechanism depended on the p53 gene. Furthermore, in vivo experiments and the colony formation experiment demonstrated that MDM2 could promote tumor progression and induce EMT via the B-Raf signaling pathway. Since EMT contributes to increased drug resistance in tumor cells, the present study also explored the relationship between MDM2 and drug sensitivity using an MTT assay, and identified that MDM2 promoted cell insensitivity to silibinin treatment in an EMT-dependent manner. This finding is crucial for the development of cancer therapies and can also provide novel research avenues for future biological and clinical studies.
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Affiliation(s)
- Mengting Ou
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China
| | - Xichao Xu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China
| | - Ying Chen
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China
| | - Li Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China
| | - Lu Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China
| | - Yi Liao
- Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400044, P.R. China
| | - Weichao Sun
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China
| | - Christine Quach
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Jianguo Feng
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China
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13
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László L, Kurilla A, Takács T, Kudlik G, Koprivanacz K, Buday L, Vas V. Recent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology. Cells 2021; 10:667. [PMID: 33802849 PMCID: PMC8002639 DOI: 10.3390/cells10030667] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/03/2021] [Accepted: 03/10/2021] [Indexed: 12/17/2022] Open
Abstract
The most commonly mutated isoform of RAS among all cancer subtypes is KRAS. In this review, we focus on the special role of KRAS mutations in colorectal cancer (CRC), aiming to collect recent data on KRAS-driven enhanced cell signalling, in vitro and in vivo research models, and CRC development-related processes such as metastasis and cancer stem cell formation. We attempt to cover the diverse nature of the effects of KRAS mutations on age-related CRC development. As the incidence of CRC is rising in young adults, we have reviewed the driving forces of ageing-dependent CRC.
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Affiliation(s)
- Loretta László
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Anita Kurilla
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Tamás Takács
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Gyöngyi Kudlik
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Kitti Koprivanacz
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - László Buday
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
- Department of Medical Chemistry, Semmelweis University Medical School, 1071 Budapest, Hungary
| | - Virag Vas
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
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14
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Mauri G, Bonazzina E, Amatu A, Tosi F, Bencardino K, Gori V, Massihnia D, Cipani T, Spina F, Ghezzi S, Siena S, Sartore-Bianchi A. The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer. Cancers (Basel) 2021; 13:E137. [PMID: 33406649 PMCID: PMC7795863 DOI: 10.3390/cancers13010137] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 12/20/2022] Open
Abstract
The BRAFV600E mutation is found in 8-10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.
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Affiliation(s)
- Gianluca Mauri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
| | - Erica Bonazzina
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Alessio Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Federica Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Katia Bencardino
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Viviana Gori
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
| | - Daniela Massihnia
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
| | - Tiziana Cipani
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Francesco Spina
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Silvia Ghezzi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
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15
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Mele L, Del Vecchio V, Marampon F, Regad T, Wagner S, Mosca L, Bimonte S, Giudice A, Liccardo D, Prisco C, Schwerdtfeger M, La Noce M, Tirino V, Caraglia M, Papaccio G, Desiderio V, Barbieri A. β 2-AR blockade potentiates MEK1/2 inhibitor effect on HNSCC by regulating the Nrf2-mediated defense mechanism. Cell Death Dis 2020; 11:850. [PMID: 33051434 PMCID: PMC7555890 DOI: 10.1038/s41419-020-03056-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/11/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023]
Abstract
The β2-Adrenergic receptor (β2-AR) is a G protein-coupled receptor (GPCR), involved in the development of many cancers, among which HNSCC. In this contest, β2-AR signaling interacts with different pathways, such as PI3K and MAPK, commonly activated by TK receptors. For this reason, TK blockade is one of the most adopted therapeutic strategies in HNSCC patients. In our study we investigated the effects of the β2-AR blocking in HNSCC cell lines, using the selective inhibitor ICI118,551 (ICI), in combination with the MAPK inhibitor U0126. We found that ICI leads to the blocking of p38 and NF-kB oncogenic pathways, strongly affecting also the ERK and PI3K pathways. Cotreatment with U0126 displays a synergic effect on cell viability and pathway alteration. Interestingly, we found that the β2-AR blockade affects Nrf2-Keap1 stability and its nuclear translocation leading to a drastic ROS increase and oxidative stress. Our results are confirmed by a TCGA dataset analysis, showing that NFE2L2 gene is commonly overexpressed in HNSC, and correlated with a lower survival rate. In our system, the PI3K pathway inhibition culminated in the blocking of pro-survival autophagy, a mechanism normally adopted by cancer cells to became less responsive to the therapies. The mTOR expression, commonly upregulated in HNSC, was reduced in patients with disease-recurrence. It is well known that mTOR has a strong autophagy inhibition effect, therefore its downregulation promoted pro-survival autophagy, with a related increase recurrence rate. Our findings highlight for the first time the key role of β2-AR and related pathway in HNSCC cell proliferation and drug resistance, proposing it as a valuable therapeutic molecular target.
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Affiliation(s)
- Luigi Mele
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy
| | - Vitale Del Vecchio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy
| | - Francesco Marampon
- Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, 00185, Rome, Italy
| | - Tarik Regad
- The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK
| | - Sarah Wagner
- The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK
| | - Laura Mosca
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via De Crecchio, 16, 80138, Naples, Italy
| | - Sabrina Bimonte
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori-IRCCS-"Fondazione G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Aldo Giudice
- Epidemiology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Via Mariano Semmola, 80131, Naples, Italy
| | - Davide Liccardo
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy
| | - Claudia Prisco
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy
| | - Melanie Schwerdtfeger
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy
| | - Marcella La Noce
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy
| | - Virginia Tirino
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via De Crecchio, 16, 80138, Naples, Italy
| | - Gianpaolo Papaccio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy.
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli" via L. Armanni 5, 80138, Naples, Italy
| | - Antonio Barbieri
- Animal Facility, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", "Fondazione G. Pascale", Via Mariano Semmola, 80131, Naples, Italy.
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Li N, Guha U, Kim C, Ye L, Cheng J, Li F, Chia D, Wei F, Wong DTW. Longitudinal Monitoring of EGFR and PIK3CA Mutations by Saliva-Based EFIRM in Advanced NSCLC Patients With Local Ablative Therapy and Osimertinib Treatment: Two Case Reports. Front Oncol 2020; 10:1240. [PMID: 32793495 PMCID: PMC7393232 DOI: 10.3389/fonc.2020.01240] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Background: The longitudinal monitoring of actionable oncogenes in circulating tumor DNA (ctDNA) of non-small cell lung cancer (NSCLC) is crucial for clinicians to evaluate current therapeutic response and adjust therapeutic strategies. Saliva-based electric field-induced release and measurement (EFIRM) is liquid biopsy platform to that can directly detect mutation genes with a small volume of samples. Herein, we compared the effectiveness of longitudinal monitoring for the combination of epidermal growth factor receptor (EGFR) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations between saliva-based EFIRM and plasma-based platforms (ddPCR and NGS) in two advanced NSCLC patients undergoing the treatment with osimertinib before and after local ablative therapy (LAT). Patients and Methods: Two patients with unresectable advanced NSCLC were enrolled into the National Institutes of Health Clinical Center (NIHCC) Study (ClinicalTrials.gov: 16-C-0092; local ablative therapy for the treatment of oligoprogressive, EGFR-mutated, non-small cell lung cancer after treatment with osimertinib). Serial collections of saliva, plasma, and metastatic tumor volume measurement by computed tomography (CT) were performed. Longitudinal paired saliva and plasma samples were analyzed for p.L858R EGFR, exon19 del EGFR, and p.E545K PIK3CA ctDNA using EFIRM (saliva) and ddPCR and NGS (plasma). Results: In Case 1, the saliva ctDNA curve of exon19 del EGFR by EFIRM demonstrated a strong similarity to those of tumor volume (R = 0.78, P = 0.00) and exon19 del EGFR in ddPCR (R = 0.53, P = 0.01). Moreover, the curve of p.E545K PIK3CA in EFIRM showed similarity to those of tumor volume (R = 0.70, P = 0.00) and p.E545K PIK3CA in NGS (R = 0.72, P = 0.00). In Case 2, the curve of p.E545K PIK3CA in EFIRM revealed a reverse relationship to that of tumor volume (R = -0.65, P = 0.01). Conclusion: In these two case reports, saliva-based EFIRM platform demonstrates a high level of concordance to plasma-based platforms (ddPCR and NGS) for longitudinally monitoring the combination of EGFR and PIK3CA ctDNA and can be a useful platform to monitor tumor progression and response to targeted therapy in NSCLC patients.
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Affiliation(s)
- Ning Li
- Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Udayan Guha
- Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
| | - Chul Kim
- Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
| | - Leah Ye
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Jordan Cheng
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Feng Li
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - David Chia
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Fang Wei
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - David T. W. Wong
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
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17
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Proto MC, Fiore D, Forte G, Cuozzo P, Ramunno A, Fattorusso C, Gazzerro P, Pascale M, Franceschelli S. Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells. Invest New Drugs 2020; 38:634-649. [PMID: 31240514 DOI: 10.1007/s10637-019-00813-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 06/06/2019] [Indexed: 01/27/2023]
Abstract
Cutaneous melanoma, the most aggressive form of skin cancer, is characterized by activating BRAF mutations. Despite the initial success of selective BRAF inhibitors, only few patients exhibited complete responses, whereas many showed disease progression. Melanoma is one of the few types of cancer in which p53 is not frequently mutated, but p53 inactivation can be indirectly achieved by a stable activation of MDM2 induced by a deletion in CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) locus, encoding for p16INK4A and p14ARF, two tumor suppressor genes. In this study, we tested the efficacy of the previously synthesized tetra-substituted pyrrole derivatives, 8 g, 8 h and 8i, in melanoma cell lines, and we compared the effects of the most active of these, the 8i compound, with that exerted by Nutlin 3, a well-known inhibitor of p53-MDM2 interaction. The obtained results showed that 8i potentiates the inhibitory effect of Nutlin 3 and the combined use of 8i and Nutlin 3 triggers apoptosis and significantly impairs melanoma viability. Finally, the 8i compound reduces p53-MDM2 interaction and induces p53-HSP90 complex formation, suggesting that the observed raise in p53 transcriptional activity could be mediated by HSP90. Because the main feature of melanoma is the resistance to most chemotherapeutics, our studies suggest that the 8i tetra-substituted pyrrole derivative, restoring p53 functions and its transcriptional activities, may have potential application, at least as adjuvant, in the treatment of human melanoma.
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Affiliation(s)
| | - Donatella Fiore
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy
| | - Giovanni Forte
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy
| | - Paola Cuozzo
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy
| | - Anna Ramunno
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy
| | | | | | - Maria Pascale
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy
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Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy. Cells 2020; 9:cells9051176. [PMID: 32397368 PMCID: PMC7291050 DOI: 10.3390/cells9051176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/14/2022] Open
Abstract
The tumor suppressor p53 is believed to be the mostly studied molecule in modern biomedical research. Although p53 interacts with hundreds of molecules to exert its biological functions, there are only a few modulators regulating its expression and function, with murine double minute 2 (MDM2) playing a key role in this regard. MDM2 also contributes to malignant transformation and cancer development through p53-dependent and -independent mechanisms. There is an increasing interest in developing MDM2 inhibitors for cancer prevention and therapy. We recently demonstrated that the nuclear factor of activated T cells 1 (NFAT1) activates MDM2 expression. NFAT1 regulates several cellular functions in cancer cells, such as cell proliferation, migration, invasion, angiogenesis, and drug resistance. Both NFAT isoforms and MDM2 are activated and overexpressed in several cancer subtypes. In addition, a positive correlation exists between NFAT1 and MDM2 in tumor tissues. Our recent clinical study has demonstrated that high expression levels of NFAT1 and MDM2 are independent predictors of a poor prognosis in patients with hepatocellular carcinoma. Thus, inhibition of the NFAT1-MDM2 pathway appears to be a novel potential therapeutic strategy for cancer. In this review, we summarize the potential oncogenic roles of MDM2 and NFAT1 in cancer cells and discuss the efforts of discovery and the development of several newly identified MDM2 and NFAT1 inhibitors, focusing on their potent in vitro and in vivo anticancer activities. This review also highlights strategies and future directions, including the need to focus on the development of more specific and effective NFAT1-MDM2 dual inhibitors for cancer therapy.
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Rusiecki R, Witkowski J, Jaszczewska-Adamczak J. MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present). Recent Pat Anticancer Drug Discov 2020; 14:324-369. [DOI: 10.2174/1574892814666191022163540] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 10/09/2019] [Accepted: 10/15/2019] [Indexed: 01/10/2023]
Abstract
Background:
Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor
suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer
therapy.
Objective:
This updated patent review is an attempt to compile the research and achievements of the
various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an
outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most
relevant patents which have recently appeared in the literature.
Methods:
Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction
inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective
compounds which are or were examined in clinical trials.
Results:
Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types
of cancer or non-cancer diseases. A great number of patents and research work around new MDM2-
p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years
prove that this targeted therapy is in the scope of interest for many business and academic research
groups.
Conclusion:
Novel MDM2 inhibitors thanks to higher potency and better ADME properties have
shown effectiveness in preclinical and clinical development however the final improvement of therapeutic
potential for MDM2 inhibitors might depend on the useful combination therapy and exploring
new cancer and non-cancer indications.
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Affiliation(s)
- Rafał Rusiecki
- Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, Warsaw 00-664, Poland
| | - Jakub Witkowski
- Faculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland
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20
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Long-term cultivation using ineffective MDM2 inhibitor concentrations alters the drug sensitivity profiles of PL21 leukaemia cells. EXPERIMENTAL RESULTS 2020. [DOI: 10.1017/exp.2019.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
AbstractAcquired MDM2 inhibitor resistance is commonly caused by loss-of-function TP53 mutations. In addition to the selection of TP53-mutant cells by MDM2 inhibitors, MDM2 inhibitor-induced DNA damage may promote the formation of TP53 mutations. Here, we cultivated 12 sublines of the intrinsically MDM2 inhibitor-resistant TP53 wild-type acute myeloid leukaemia cell line PL21 for 52 passages in the presence of ineffective concentrations of the MDM2 inhibitor nutlin-3 but did not observe loss-of-function TP53 mutations. This suggests that MDM2 inhibitors select TP53-mutant cells after mutations have occurred, but do not directly promote TP53 mutations. Unexpectedly, many sublines displayed increased sensitivity to the anti-cancer drugs cytarabine, doxorubicin, or gemcitabine. Consequently, therapies can affect the outcome of next-line treatments, even in the absence of a therapy response. This finding is conceptually novel. A better understanding of such processes will inform the design of improved therapy protocols in the future.
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21
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He H, Xu C, Cheng Z, Qian X, Zheng L. Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers. Curr Top Med Chem 2019; 19:2128-2142. [PMID: 31475900 DOI: 10.2174/1568026619666190902150555] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/23/2019] [Accepted: 07/04/2019] [Indexed: 02/08/2023]
Abstract
KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.
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Affiliation(s)
- Hao He
- School of Pharmacy, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Chang Xu
- National Vaccine & Serum Institute, Beijing, China
| | - Zhao Cheng
- School of Pharmacy, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Xiaoying Qian
- School of Pharmacy, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Lei Zheng
- School of Pharmacy, Xi'an Medical University, Xi'an, Shaanxi, China
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22
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Wu HZ, Xiao JQ, Xiao SS, Cheng Y. KRAS: A Promising Therapeutic Target for Cancer Treatment. Curr Top Med Chem 2019; 19:2081-2097. [PMID: 31486755 DOI: 10.2174/1568026619666190905164144] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 07/19/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023]
Abstract
Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most commonly mutated oncogene in human cancer. The developments of many cancers depend on sustained expression and signaling of KRAS, which makes KRAS a high-priority therapeutic target. Scientists have not successfully developed drugs that target KRAS, although efforts have been made last three decades. In this review, we highlight the emerging experimental strategies of impairing KRAS membrane localization and the direct targeting of KRAS. We also conclude the combinatorial therapies and RNA interference technology for the treatment of KRAS mutant cancers. Moreover, the virtual screening approach to discover novel KRAS inhibitors and synthetic lethality interactors of KRAS are discussed in detail.
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Affiliation(s)
- Hai-Zhou Wu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China
| | - Jia-Qi Xiao
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China
| | - Song-Shu Xiao
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yan Cheng
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China
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23
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Michaelis M, Wass MN, Cinatl J. Drug-adapted cancer cell lines as preclinical models of acquired resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:447-456. [PMID: 35582596 PMCID: PMC8992517 DOI: 10.20517/cdr.2019.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 05/17/2019] [Accepted: 05/23/2019] [Indexed: 12/12/2022]
Abstract
Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.
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Affiliation(s)
- Martin Michaelis
- School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK
| | - Mark N Wass
- School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK
| | - Jindrich Cinatl
- Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany
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24
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Erba HP, Becker PS, Shami PJ, Grunwald MR, Flesher DL, Zhu M, Rasmussen E, Henary HA, Anderson AA, Wang ES. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv 2019; 3:1939-1949. [PMID: 31253596 PMCID: PMC6616264 DOI: 10.1182/bloodadvances.2019030916] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 05/10/2019] [Indexed: 12/18/2022] Open
Abstract
This open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.
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Affiliation(s)
- Harry P Erba
- Division of Hematologic Malignancies and Cellular Therapy, Department of Internal Medicine, Duke University, Durham, NC
| | - Pamela S Becker
- Division of Hematology, University of Washington School of Medicine, Seattle, WA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Paul J Shami
- Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Michael R Grunwald
- Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC
| | | | - Min Zhu
- Amgen Inc., Thousand Oaks, CA; and
| | | | | | | | - Eunice S Wang
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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25
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Wang H, Li F, Liu N, Liu X, Yang X, Guo Y, Bei J, Zeng Y, Shao J. Prognostic implications of a molecular classifier derived from whole-exome sequencing in nasopharyngeal carcinoma. Cancer Med 2019; 8:2705-2716. [PMID: 30950204 PMCID: PMC6558473 DOI: 10.1002/cam4.2146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 03/04/2019] [Accepted: 03/07/2019] [Indexed: 12/30/2022] Open
Abstract
The aim of this study was to use whole-exome sequencing to derive a molecular classifier for nasopharyngeal carcinoma (NPC) and evaluate its clinical performance. We performed whole-exome sequencing on 82 primary NPC tumors from Sun Yat-sen University Cancer Center (Guangzhou cohort) to obtain somatic single-nucleotide variants, indels, and copy number variants. A novel molecular classifier was then developed and validated in another NPC cohort (Hong Kong cohort, n = 99). Survival analysis was estimated by the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards model was adopted for univariate and multivariate analyses. We identified three prominent NPC genetic subtypes: RAS/PI3K/AKT (based on RAS, AKT1, and PIK3CA mutations), cell-cycle (based on CDKN2A/CDKN2B deletions, and CDKN1B and CCND1 amplifications), and unclassified (based on dominant mutations in epigenetic regulators, such as KMT2C/2D, or the Notch signaling pathway, such as NOTCH1/2). These subtypes differed in survival analysis, with good, intermediate, and poor progression-free survival in the unclassified, cell-cycle, and RAS/PI3K/AKT subgroups, respectively, among the Guangzhou, Hong Kong, and combined cohorts (n = 82, P = 0.0342; n = 99, P = 0.0372; and n = 181, P = 0.0023; log-rank test). We have uncovered genetic subtypes of NPC with distinct mutations and/or copy number changes, reflecting discrete paths of NPC tumorigenesis and providing a roadmap for developing new prognostic biomarkers and targeted therapies.
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Affiliation(s)
- Hai‐Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Molecular DiagnosticsSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Fugen Li
- Research and Development Institute of Precision Medicine3D Medicine Inc.ShanghaiP. R. China
| | - Na Liu
- BGI Genomics, BGI‐ShenzhenShenzhenP. R. China
| | - Xiao‐Yun Liu
- Department of Molecular DiagnosticsSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Xin‐Hua Yang
- Department of Molecular DiagnosticsSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Yun‐Miao Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Experiment ResearchSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Jin‐Xin Bei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Experiment ResearchSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Yi‐Xin Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Experiment ResearchSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Jian‐Yong Shao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Molecular DiagnosticsSun Yat‐sen University Cancer CenterGuangzhouP. R. China
- School of Laboratory MedicineWannan Medical CollegeWuhu, Anhui ProvinceP. R. China
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Xu N, Hua Z, Ba G, Zhang S, Liu Z, Thiele CJ, Li Z. The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:118. [PMID: 30850026 PMCID: PMC6408795 DOI: 10.1186/s13046-019-1107-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 02/14/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children with poor survival. New treatment approaches are urgently needed to improve treatment efficacy in RMS patients. DMAMCL is a novel agent from Asteraceae family that has been tested in phase I clinical trials in adult glioma in Australia. METHODS Five RMS cell lines (RD, RH18, RH28, RH30 and RH41) were used. The in vitro anti-tumor effect of DMAMCL, alone or in combination with VCR or Epirubicin, was studied using MTS assay or IncuCyte-Zoom cell confluency assay, and further validated by xenograft-mouse model in vivo. Changes in caspase-3/7 activity, cell-cycle progression and generation of ROS after DMAMCL treatment were investigated. Bim mRNA expression was measured by RT-qPCR, and protein expressions of Bim and phosphorylated-NF-κB(p65) by Western blotting. Small interfering RNAs (siRNA) of Bim were used to study the role of Bim in DMAMCL-induced cell death. RESULTS In vitro, DMAMCL treatment induced a dose-dependent increase in cell death that could be blocked by pan-caspase-inhibitor-Z-VAD-fmk in five RMS cell lines. The percent of cells in SubG1 phase and activities of caspase-3/7 increased after DMAMCL treatment; The combination of DMAMCL with VCR or Epirubicin significantly increased cell death compared to each reagent alone. In vivo, DMAMCL(75 mg/kg or 100 mg/kg) inhibited tumor growth and prolonged survival of mice bearing xenograft RMS tumors (RD, RH18, RH30, RH41). Compared to treatment with DMAMCL or VCR, a combination of two reagents caused significant inhibition of tumor growth (RD, RH41), even after treatment termination. The expression of Bim increased at protein level after DMAMCL treatment both in vitro and in vivo. The expression of p-NF-κB(p65) had a transient increase and the generation of ROS increased after DMAMCL treatment in vitro. Transfection of Bim siRNA into RMS cells blocked the DMAMCL-induced increase of Bim and partially attenuated the DMAMCL-induced cell death. CONCLUSION DMAMCL had an anti-tumor growth effect in vitro and in vivo that potentially mediated by Bim, NF-κB pathway and ROS. A combination of DMAMCL with chemotherapeutic drugs significantly increased the treatment efficacy. Our study supports further clinical evaluation of DMAMCL in combination with conventional chemotherapy.
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Affiliation(s)
- Ning Xu
- Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Zhongyan Hua
- Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Gen Ba
- Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Simeng Zhang
- Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Zhihui Liu
- Cellular & Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Carol J Thiele
- Cellular & Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Zhijie Li
- Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Targeting ALK in Cancer: Therapeutic Potential of Proapoptotic Peptides. Cancers (Basel) 2019; 11:cancers11030275. [PMID: 30813562 PMCID: PMC6468335 DOI: 10.3390/cancers11030275] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/13/2019] [Accepted: 02/21/2019] [Indexed: 01/30/2023] Open
Abstract
ALK is a receptor tyrosine kinase, associated with many tumor types as diverse as anaplastic large cell lymphomas, inflammatory myofibroblastic tumors, breast and renal cell carcinomas, non-small cell lung cancer, neuroblastomas, and more. This makes ALK an attractive target for cancer therapy. Since ALK–driven tumors are dependent for their proliferation on the constitutively activated ALK kinase, a number of tyrosine kinase inhibitors have been developed to block tumor growth. While some inhibitors are under investigation in clinical trials, others are now approved for treatment, notably in ALK-positive lung cancer. Their efficacy is remarkable, however limited in time, as the tumors escape and become resistant to the treatment through different mechanisms. Hence, there is a pressing need to target ALK-dependent tumors by other therapeutic strategies, and possibly use them in combination with kinase inhibitors. In this review we will focus on the therapeutic potential of proapoptotic ALK-derived peptides based on the dependence receptor properties of ALK. We will also try to make a non-exhaustive list of several alternative treatments targeting ALK-dependent and independent signaling pathways.
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Berberich A, Kessler T, Thomé CM, Pusch S, Hielscher T, Sahm F, Oezen I, Schmitt LM, Ciprut S, Hucke N, Ruebmann P, Fischer M, Lemke D, Breckwoldt MO, von Deimling A, Bendszus M, Platten M, Wick W. Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib. Clin Cancer Res 2018; 25:253-265. [DOI: 10.1158/1078-0432.ccr-18-1580] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 08/07/2018] [Accepted: 09/27/2018] [Indexed: 11/16/2022]
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MEK inhibitors induce apoptosis via FoxO3a-dependent PUMA induction in colorectal cancer cells. Oncogenesis 2018; 7:67. [PMID: 30190455 PMCID: PMC6127344 DOI: 10.1038/s41389-018-0078-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 07/07/2018] [Accepted: 07/30/2018] [Indexed: 12/19/2022] Open
Abstract
Mutations in BRAF are common to many cancers, including CRC. The MEK inhibitors are being investigated in BRAF-mutant CRC. In this study, we aimed to investigate how MEK inhibitor suppresses growth of BRAF-mutated CRC cells as well as its potential mechanisms. Our findings indicated that MEK inhibitor promote PUMA expression via ERK/FoxO3a signaling pathway. In addition, PUMA induction is essential for MEK inhibitor-induced apoptosis. Moreover, PUMA induction is required for MEK inhibitors to induced apoptosis in combination with cisplatin, dabrafenib, or Gefitinib. Knockdown of PUMA suppressed the anticancer effect of the MEK inhibitor in vivo. Our findings indicate a novel role for PUMA as a regulator of the antitumor effects of MEK inhibitor, suggesting that PUMA induction may modulate MEK inhibitor sensitivity.
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