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1
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Xiao X, Xu R, Lu J, Xin B, Wang C, Zhu K, Zhang H, Chen X. The potential role of next-generation sequencing in identifying MET amplification and disclosing resistance mechanisms in NSCLC patients with osimertinib resistance. Front Oncol 2024; 14:1470827. [PMID: 39497720 PMCID: PMC11532092 DOI: 10.3389/fonc.2024.1470827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/07/2024] [Indexed: 11/07/2024] Open
Abstract
Purposes Osimertinib, one of the third-generation EGFR-tyrosine kinase inhibitors (TKIs) designed to target EGFR T790M mutation, significantly improves the prognosis of lung cancer. However, drug resistance still happens and MET amplification is responsible for one of the main causes. Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection, but fundamentally limited by observer subjectivity. Herein, we assessed the value of next-generation sequencing (NGS) method in MET amplification detection in non-small cell lung cancer (NSCLC), as well as revealed the mutation profiling of NSCLC patients with osimertinib resistance to provide some valuable clues to the mechanisms of resistance. Methods A total of 317 cancer tissue samples from 317 NSCLC patients at time of progression following osimertinib were submitted to NGS and only 96 tissues were tested by FISH simultaneously. With FISH results as gold standard, enumeration algorithm was applied to establish the optimal model for identifying MET amplification using gene copy number (GCN) data. Results The optimal model for identifying MET amplification was constructed based on the GCN of MET, BRAF, CDK6 and CYP3A4, which achieved a 74.0% overall agreement with FISH and performed well in identifying MET amplification except polysomy with a sensitivity of 85.7% and a specificity of 93.9%. The inconsistency between NGS and FISH occurred mainly in polysomy subtype, while MET GCN ≥ 5 could be reliably recognized by NGS. Moreover, the most frequently mutated genes in NSCLC patients with osimertinib resistance were EGFR (59.94%), followed by TP53 (43.85%), NRG1 (9.46%), PIK3CA (6.31%), and ATM (5.36%). The known resistance mechanisms, including MET amplification, EGFR (C797S, L718Q/R), TP53, CDK4, CDK6, CDKN2A, BRAF, KRAS, NRAS and PIK3CA mutations were also disclosed in our cohort. Conclusions NGS assay can achieve a high concordance with FISH in MET amplification detection and has advantages in portraying various genetic alterations, which is of worthy in clinical promotion.
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Affiliation(s)
- Xiao Xiao
- School of Physics, Changchun University of Science and Technology, Changchun, China
- Research & Development Department, Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China
| | - Ren Xu
- School of Physics, Changchun University of Science and Technology, Changchun, China
- Research & Development Department, Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China
| | - Jun Lu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Beibei Xin
- Research & Development Department, Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China
| | - Chenyang Wang
- Research & Development Department, Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China
| | - Kexin Zhu
- Research & Development Department, Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China
| | - Hao Zhang
- School of Life Science and Technology, Changchun University of Science and Technology, Changchun, China
| | - Xinyu Chen
- School of Physics, Changchun University of Science and Technology, Changchun, China
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Wang Y, Wei J, Xu M, Xiang J, Shao K, Hao Y, Song Z. Efficacy and safety analysis of immunotherapy in non-small cell lung cancer patients with MET alterations. Clin Transl Oncol 2024; 26:2503-2512. [PMID: 38627317 DOI: 10.1007/s12094-024-03455-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 03/06/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND Mesenchymal epithelial transition factor (MET) is a rare oncologic driver gene, and information on immunotherapy for non-small cell lung cancer (NSCLC) patients with this driver gene is limited. Here we evaluate the efficacy and safety of immune checkpoint inhibitors (ICI) under different therapeutic regimen for NSCLC patients with MET alterations. METHODS From June 2019 to December 2023, we assessed the efficacy and toxicity of ICIs in 42 NSCLC patients with MET alterations. Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazards model applied for univariate and multivariate analyses. We assessed the size of target lesion according to RECIST v1.1, and objective response rate (ORR) was defined as the sum of complete response (CR) and partial response (PR), disease control rate (DCR) as the sum of CR, PR, and disease stable. RESULTS A total of 42 NSCLC patients with MET alterations were included in this retrospective study, 10 was MET 14 skipping mutation and 32 was MET amplification. The ORR for ICI treatment was 30.95% and the DCR was 71.43%. Median progression-free survival (mPFS) and median overall survival (OS) were 4.40 and 13.97 months, respectively. There exists statistical differences between the mPFS of ICI monotherapy and combine ICI therapy (2.8 vs 7.8 months, p = 0.022). The incidence of drug-related adverse reactions was 47.62%, mainly bone marrow suppression (14.28%), immune-related pneumonia (7.14%), and liver function impairment (7.14%), and six patients (14.28%) experiencing grade 3 or above adverse events. CONCLUSION NSCLC patients with MET alterations can benefit from immunotherapy, especially the patients treated by combined ICI therapy. However, special attention should be paid to the occurrence of grade 3/4 adverse reactions while using the combined ICI therapy.
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Affiliation(s)
- Yanhua Wang
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310000, China
- Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Jingwen Wei
- Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Manyi Xu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310000, China
- Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Jing Xiang
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310000, China
- Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Keda Shao
- Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Yue Hao
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310000, China.
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China.
- Department of Clinical Trial, Zhejiang Cancer Hospital, No.1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China.
| | - Zhengbo Song
- Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China.
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China.
- Department of Clinical Trial, Zhejiang Cancer Hospital, No.1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China.
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Yuan P, Xue X, Qiu T, Ying J. MET alterations detection platforms and clinical implications in solid tumors: a comprehensive review of literature. Ther Adv Med Oncol 2024; 16:17588359231221910. [PMID: 38249331 PMCID: PMC10798113 DOI: 10.1177/17588359231221910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 12/04/2023] [Indexed: 01/23/2024] Open
Abstract
MET alterations, including MET exon 14 skipping variants, MET amplification, MET overexpression, and MET fusion, play pivotal roles in primary tumorigenesis and acquired resistance to targeted therapies, especially EGFR tyrosine kinase inhibitors. They represent important diagnostic, prognostic, and predictive biomarkers in many solid tumor types. However, the detection of MET alterations is challenging due to the complexity of MET alterations and the diversity of platform technologies. Therefore, techniques with high sensitivity, specificity, and reliable molecular detection accuracy are needed to overcome such hindrances and aid in biomarker-guided therapies. The current review emphasizes the role of MET alterations as oncogenic drivers in a variety of cancers and their involvement in the development of resistance to targeted therapies. Moreover, our review provides an overview of and recommendations on the selection of various cross-platform technologies for the detection of MET exon 14 skipping variants, MET amplification, MET overexpression, and MET fusion. Furthermore, challenges and hurdles underlying these common detection platforms are discussed.
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Affiliation(s)
- Pei Yuan
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuemin Xue
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tian Qiu
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianming Ying
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
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4
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Benkhoucha M, Tran NL, Senoner I, Breville G, Fritah H, Migliorini D, Dutoit V, Lalive PH. c-Met + Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models. Biomedicines 2023; 11:3123. [PMID: 38137344 PMCID: PMC10740932 DOI: 10.3390/biomedicines11123123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/13/2023] [Accepted: 11/16/2023] [Indexed: 12/24/2023] Open
Abstract
CD8+ cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, we identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor, c-Met (c-Met+ CTLs), that are endowed with enhanced cytolytic capacity. HGF directly inhibited the cytolytic function of c-Met+ CTLs, both in 2D in vitro assays and in vivo, leading to reduced T cell responses against metastatic melanoma. To further investigate the role of c-Met+ CTLs in a three-dimensional (3D) setting, we studied their function within B16 melanoma spheroids and examined the impact of cell-cell contact on the modulation of inhibitory checkpoint molecules' expression, such as KLRG1, PD-1, and CTLA-4. Additionally, we evaluated the cytolytic capacity of human CTL clones expressing c-Met (c-Met+) and compared it to c-Met- CTL clones. Our results indicated that, similar to their murine counterparts, c-Met+ human CTL clones exhibited increased cytolytic activity compared to c-Met- CTL clones, and this enhanced function was negatively regulated by the presence of HGF. Taken together, our findings highlight the potential of targeting the HGF/c-Met pathway to modulate CTL-mediated anti-tumor immunity. This research holds promise for developing strategies to enhance the effectiveness of CTL-based immunotherapies against cancer.
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Affiliation(s)
- Mahdia Benkhoucha
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.B.); (N.L.T.); (I.S.); (H.F.)
| | - Ngoc Lan Tran
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.B.); (N.L.T.); (I.S.); (H.F.)
| | - Isis Senoner
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.B.); (N.L.T.); (I.S.); (H.F.)
| | - Gautier Breville
- Department of Clinical Neurosciences, Division of Neurology, University Hospital of Geneva, 1205 Geneva, Switzerland;
- Center for Neuroinflammation and Experimental Therapeutics, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hajer Fritah
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.B.); (N.L.T.); (I.S.); (H.F.)
| | - Denis Migliorini
- Brain Tumor and Immune Cell Engineering Laboratory, Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (D.M.); (V.D.)
- Department of Oncology, Unit of Neuro-Oncology, University Hospital of Geneva, 1205 Geneva, Switzerland
| | - Valérie Dutoit
- Brain Tumor and Immune Cell Engineering Laboratory, Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (D.M.); (V.D.)
| | - Patrice H. Lalive
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.B.); (N.L.T.); (I.S.); (H.F.)
- Department of Clinical Neurosciences, Division of Neurology, University Hospital of Geneva, 1205 Geneva, Switzerland;
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Zhang M, Zhang Z, Tian X, Zhang E, Wang Y, Tang J, Zhao J. NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor. Front Pharmacol 2023; 14:1291773. [PMID: 38027016 PMCID: PMC10666796 DOI: 10.3389/fphar.2023.1291773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023] Open
Abstract
Tumorigenesis and tumor development are closely related to the abnormal regulation of ubiquitination. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin ligase critical to the ubiquitination process, plays key roles in the regulation of cancer stem cells, as well as tumor cell functions, including cell proliferation, apoptosis, cell cycle regulation, migration, invasion, epithelial-mesenchymal transition (EMT), and tumor drug resistance, by controlling subsequent protein degradation through ubiquitination. NEDD4L primarily functions as a tumor suppressor in several tumors but also plays an oncogenic role in certain tumors. In this review, we comprehensively summarize the relevant signaling pathways of NEDD4L in tumors, the regulatory mechanisms of its upstream regulatory molecules and downstream substrates, and the resulting functional alterations. Overall, therapeutic strategies targeting NEDD4L to treat cancer may be feasible.
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Affiliation(s)
- Meng Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhenyong Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xin Tian
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Enchong Zhang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yichun Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jun Tang
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jianzhu Zhao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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Feng J, Leng J, Zhao C, Guo J, Chen Y, Li H. High expression of 14-3-3ơ indicates poor prognosis and progression of lung adenocarcinoma. Oncol Lett 2022; 24:203. [PMID: 35720477 PMCID: PMC9178702 DOI: 10.3892/ol.2022.13323] [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: 02/18/2022] [Accepted: 04/13/2022] [Indexed: 11/06/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death worldwide. 14-3-3ơ is an intracellular phosphoserine-binding protein that has been proposed to be involved in tumorigenesis. However, the biofunctional role of 14-3-3ơ and its clinicopathological/prognostic significance in LUAD have remained elusive. In the present study, western blot and immunohistochemical analyses of cancer tissues/cells and the corresponding normal controls were performed to verify that 14-3-3ơ was upregulated in LUAD. Univariate and multivariate logistic regression analysis indicated that high expression of 14-3-3ơ predicted poor overall survival and progression-free survival of patients with LUAD. Furthermore, in vivo and in vitro experiments demonstrated that overexpression of 14-3-3ơ markedly promoted cell proliferation, colony formation, anchorage-independent growth and tumor growth, whereas 14-3-3ơ depletion produced the opposite effects. Of note, 14-3-3ơ was identified as an independent prognostic factor for patients with LUAD. Collectively, the present results revealed that high expression of 14-3-3ơ may serve as an independent biomarker, contributing to poor prognosis and progression of LUAD.
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Affiliation(s)
- Junfei Feng
- Department of Respiratory and Critical Care Medicine, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, P.R. China
| | - Jing Leng
- Department of Respiratory and Critical Care Medicine, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, P.R. China
| | - Changdi Zhao
- Department of Respiratory and Critical Care Medicine, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, P.R. China
| | - Jie Guo
- Department of Respiratory and Critical Care Medicine, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, P.R. China
| | - Yongbing Chen
- Department of Respiratory Medicine, People's Hospital of Beilun District, Ningbo, Zhejiang 315826, P.R. China
| | - Haifeng Li
- Department of Respiratory and Critical Care Medicine, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, P.R. China
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López-Castro R, García-Peña T, Mielgo-Rubio X, Riudavets M, Teixidó C, Vilariño N, Couñago F, Mezquita L. Targeting molecular alterations in non-small-cell lung cancer: what's next? Per Med 2022; 19:341-359. [PMID: 35748237 DOI: 10.2217/pme-2021-0059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In recent years, major advances have been achieved in our understanding of non-small-cell lung cancer (NSCLC) with oncogenic driver alterations and in the specific treatment of these with tyrosine kinase inhibitors. Currently, state-of-the-art management of patients with NSCLC (particularly adenocarcinoma or non-adenocarcinoma but with mild tobacco exposure) consists of the determination of EGFR, ALK, ROS1 and BRAF status, as they have US FDA and EMA approved targeted therapies. The increase in molecular knowledge of NSCLC and the development of drugs against other targets has settled new therapeutic indications. In this review we have incorporated the development around MET, KRAS and NTRK in the diagnosis of NSCLC given the therapeutic potential that they represent, as well as the drugs approved for these indications.
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Affiliation(s)
- Rafael López-Castro
- Medical Oncology Department, Hospital Clínico Universitario de Valladolid, Valladolid, 47003, Spain
| | - Tania García-Peña
- Medical Oncology Department, Hospital Clínico Universitario de Valladolid, Valladolid, 47003, Spain
| | - Xabier Mielgo-Rubio
- Medical Oncology Department, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, 28922, Spain
| | - Mariona Riudavets
- Medical Oncology Department, Gustave Roussy Cancer Campus, Villejuif, 94805, France
| | - Cristina Teixidó
- Thoracic Tumors Unit, Pathology Department, Hospital Clinic of Barcelona, Barcelona, 08036, Spain
| | - Noelia Vilariño
- Medical Oncology Department, Catalan Institute of Oncology, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, 08908, Spain
| | - Felipe Couñago
- Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón, Madrid, 28223, Spain.,Department of Radiation Oncology, Hospital La Luz, Madrid, 28003, Spain.,Medicine Department, School of Biomedical Sciences, Universidad Europea, Villaviciosa de Odón, Madrid, 28670, Spain
| | - Laura Mezquita
- Thoracic Tumors Unit, Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, 08036, Spain
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Patnaik A, Gadgeel S, Papadopoulos KP, Rasco DW, Haas NB, Der-Torossian H, Faltaos D, Potvin D, Tassell V, Tawashi M, Chao R, O'Dwyer PJ. Phase I Study of Glesatinib (MGCD256) in Combination with Erlotinib or Docetaxel in Patients with Advanced Solid Tumors. Target Oncol 2022; 17:125-138. [PMID: 35347559 DOI: 10.1007/s11523-022-00875-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Oncogenic drivers in solid tumors include aberrant activation of mesenchymal epithelial transition factor (MET) and AXL. OBJECTIVE This study investigated the safety and antitumor activity of glesatinib, a multitargeted receptor tyrosine kinase inhibitor that inhibits MET and AXL at clinically relevant doses, in combination with erlotinib or docetaxel. PATIENTS AND METHODS The phase I portion of this open-label, multicenter study included two parallel arms in which ascending doses of oral glesatinib (starting dose 96 mg/m2) were administered with erlotinib or docetaxel (starting doses 100 mg once daily and 50 mg/m2, respectively) using a modified 3 + 3 design. Maximum tolerated dose (MTD) was based on dose-limiting toxicities (DLTs) during the first 21-day treatment cycle. Enrollment focused on patients with solid tumor types typically associated with MET aberration and/or AXL overexpression. The primary objective was to determine the safety profile of the treatment combinations. Antitumor activity and pharmacokinetics (PK) were also assessed. RESULTS Ten dose levels of glesatinib across three glycolate formulations (unmicronized, micronized, or micronized version 2 [V2] tablets) available during the course of the study were investigated in 14 dose-escalation cohorts (n = 126). MTDs of unmicronized glesatinib plus erlotinib or docetaxel, and micronized glesatinib plus erlotinib were not reached. Micronized glesatinib 96 mg/m2 plus docetaxel exceeded the MTD. Further dosing focused on glesatinib micronized V2: maximum administered dose (MAD) was 700 mg twice daily with erlotinib 150 mg once daily or docetaxel 75 mg/m2 every 3 weeks. DLTs, acceptable at lower glesatinib (micronized V2) dose levels, occurred in two of five and two of six patients at the MADs of glesatinib + erlotinib and glesatinib + docetaxel, respectively. Across all cohorts, the most frequent treatment-related adverse events were diarrhea (glesatinib + erlotinib: 84.1%; glesatinib + docetaxel: 45.6%), fatigue (46.4%, 70.4%), and nausea (30.4%, 35.1%). The objective response rate was 1.8% and 12.0% in all glesatinib + erlotinib and glesatinib + docetaxel cohorts, respectively. CONCLUSIONS The safety profile of glesatinib plus erlotinib or docetaxel was acceptable and there were no PK interactions. MADs of glesatinib 700 mg twice daily (micronized V2) with erlotinib 150 mg once daily or docetaxel 75 mg/m2 every 3 weeks exceeded the MTD by a small margin. Modest signals of efficacy were observed with these treatment combinations in non-genetically selected patients with advanced solid tumors. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov NCT00975767; 11 September 2009.
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Affiliation(s)
- Amita Patnaik
- START, 4383 Medical Drive, Suite 4026, San Antonio, TX, 78229, USA.
| | - Shirish Gadgeel
- Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.,Henry Ford Health System, Detroit, MI, USA
| | | | - Drew W Rasco
- START, 4383 Medical Drive, Suite 4026, San Antonio, TX, 78229, USA
| | - Naomi B Haas
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Demiana Faltaos
- Mirati Therapeutics Inc., San Diego, CA, USA.,Olema Therapeutics, San Francisco, CA, USA
| | | | | | - Manal Tawashi
- Mirati Therapeutics Inc., San Diego, CA, USA.,HUYABIO International, San Diego, CA, USA
| | | | - Peter J O'Dwyer
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
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9
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Kazybay B, Ahmad A, Mu C, Mengdesh D, Xie Y. Omicron N501Y mutation among SARS-CoV-2 lineages: Insilico analysis of potent binding to tyrosine kinase and hypothetical repurposed medicine. Travel Med Infect Dis 2022; 45:102242. [PMID: 34929375 PMCID: PMC8677628 DOI: 10.1016/j.tmaid.2021.102242] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022]
Abstract
Variants of SARS-CoV-2 lineages including the most recently circulated Omicron, and previous pandemic B.1.351, B.1.1.7, which have been public concerns, contain a N501Y mutation located in the spike receptor binding domain. However, the potential interactions with host cells linking N501Y mutation to pathogenic relevance remain elusive. Recently, we and others report that kinases such as PI3K/AKT signaling are essential in SARS-CoV-2 entry. Here we analyzed the predicted potential kinases interacting with the mutation. Bioinformatics tools including structure-prediction based molecular docking analysis were applied. We found kinases such as EGFR might potentially act as new factors involving the N501Y mutation binding through possible phosphorylation at Y501 and enhanced affinity in certain variants. To our surprise, the Omicron receptor binding domain harboring N501Y mutation did not enhance binding to EGFR which might be due to the mutations of charged polar to uncharged polar side chains located on the interaction interfaces. Similarly, potent gains of phosphorylation in B.1.351 and B.1.1.7 by mutations were predicted and interaction networks were analyzed with enrichment of pathways. Given kinases might be elevated in cancer patients, the N501Y mutation containing lineages may be possibly much more infectious and additional care for cancer management might be taken into consideration by precision prevention, therapy or recovery.
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Affiliation(s)
- Bexultan Kazybay
- Biology Department, Nazarbayev University, Nur-Sultan, 010000, Kazakhstan
| | - Ashfaq Ahmad
- Department of Bioinformatics, Hazara University, Mansehra, 21300, Pakistan
| | - Chenglin Mu
- Zhejiang University, Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China
| | - Diana Mengdesh
- Biology Department, Nazarbayev University, Nur-Sultan, 010000, Kazakhstan
| | - Yingqiu Xie
- Biology Department, Nazarbayev University, Nur-Sultan, 010000, Kazakhstan.
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10
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Castiglione R, Alidousty C, Holz B, Duerbaum N, Wittersheim M, Binot E, Merkelbach-Bruse S, Friedrichs N, Dettmer MS, Bosse A, Buettner R, Schultheis AM. MET-FISH Evaluation Algorithm: Proposal of a Simplified Method. JOURNAL OF CANCER SCIENCE AND CLINICAL THERAPEUTICS 2022; 6:411-427. [PMID: 36713931 PMCID: PMC9878991 DOI: 10.26502/jcsct.5079180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
MET amplifications (METamp) occur in 5% of NSCLC and represent in most case mechanisms of resistance to ALK and/or EGFR-targeted therapies. METamp detection can be performed using different techniques, although Fluorescence In-Situ Hybridization (FISH) remains the gold-standard, especially in the context of subclonality. To date current evaluation algorithms of MET amplifications are time consuming. Aim of the study was to identify a faster, equally reliable diagnostic algorithm for the detection of METamp, which is currently classified in negativity and low/intermediate/high-level amplification. N=497 NSCLC cases with available MET-FISH data had been selected. The results based on the first evaluated 20 cells had been re-calculated and compared with the definitive results based on 60 cells. For n=464 (93.4%) identical results had been obtained when counting 20 cells instead of 60 cells. Thirty-three cases (5.6%) showed a discrepancy, leading to an incorrect upgrade to a higher diagnostic category (n=25) and to an incorrect downgrade (n=8). We propose a simplified, yet equally reliable MET FISH-algorithm: after accurate screening of the whole tumor slide, twenty tumor cells have to be evaluated and results calculated: If the result is negative, or if all criteria of high-level METamp are fulfilled, the case can be signed out as such. All other cases should be considered as equivocal and additional 40 cells have to be counted. Given that, reliable results can be obtained by counting 20 cells only and an "equivocal" category for cases that need further investigation have been clearly defined.
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Affiliation(s)
- Roberta Castiglione
- Institute of Pathology, Klinikum Stuttgart, Stuttgart, Germany
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | | | - Barbara Holz
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Nicolai Duerbaum
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Maike Wittersheim
- Institute of Pathology, Medizin Campus Bodensee, Friedrichshafen, Germany
| | - Elke Binot
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | | | | | | | - Alexander Bosse
- Institute of Pathology, Klinikum Stuttgart, Stuttgart, Germany
| | - Reinhard Buettner
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
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11
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Chen Y, Hong H, Wang Q, Li J, Zhang W, Chen T, Li P. NEDD4L-induced ubiquitination mediating UBE2T degradation inhibits progression of lung adenocarcinoma via PI3K-AKT signaling. Cancer Cell Int 2021; 21:631. [PMID: 34838005 PMCID: PMC8626996 DOI: 10.1186/s12935-021-02341-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/15/2021] [Indexed: 01/19/2023] Open
Abstract
Background A number of studies have indicated that Ubiquitin-conjugating enzyme E2T (UBE2T), as an oncogene, promotes progression and metastasis of lung cancer, including lung adenocarcinoma (LUAD), but it is completely unknown whether and how UBE2T is ubiquitylated and degraded, and by which E3 ligase. NEDD4L plays a critical role in the regulation of cellular processes of various cancers, most of which is attributed to its E3 ubiquitin ligase function. However, the relationship between NEDD4L and UBE2T in LUAD has not been elucidated. Methods The relationship between NEDD4L and UBE2T in LUAD tissues and cells was found by bioinformatic analyses and immunoblotting. Cell counting kit-8, colony formation assay, half-life analysis and the in vivo ubiquitylation assay, generation of xenograft model were performed to determine how NEDD4L regulates UBE2T and its downstream signaling pathway in vitro and in vivo. Results Bioinformatic analyses found that NEDD4L, as a potential correlation E3 ligase of UBE2T, was negatively correlated with UBE2T in LUAD. Consistently, UBE2T protein half-life was shortened or extended by NEDD4L overexpression or depletion, respectively. NEDD4L inhibited LUAD cell progression in vitro and in vivo via inducing the ubiquitination-mediated UBE2T degradation, which repressed PI3K-AKT signaling. Similarly, NEDD4L predicted a better patient survival, whereas UBE2T predicted a worse survival. Conclusions Collectively, our results reveal that NEDD4L is a novel E3 ligase of UBE2T, which can inhibit PI3K-AKT signaling by targeting for UBE2T ubiquitination and degradation, resulting in repression of LUAD cell progression.
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Affiliation(s)
- Yongbing Chen
- Department of Respiratory Medicine, Beilun Branch, Zhejiang University School of Medicine First Affiliated Hospital, Ningbo, 315800, China
| | - Haihua Hong
- Department of Respiratory Medicine, Beilun Branch, Zhejiang University School of Medicine First Affiliated Hospital, Ningbo, 315800, China
| | - Qingqing Wang
- Department of Respiratory Medicine, Beilun Branch, Zhejiang University School of Medicine First Affiliated Hospital, Ningbo, 315800, China
| | - Junqiang Li
- Department of Pathology, Beilun Branch, Zhejiang University School of Medicine First Affiliated Hospital, Ningbo, 315800, China
| | - Wenfeng Zhang
- Department of Infectious Disease, The First Affiliated Hospital, Nanchang University, Nanchang, 330052, China.
| | - Tingting Chen
- Department of Urology, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
| | - Pu Li
- State Drug Clinical Trial Agency, The First Affiliated Hospital, Nanchang University, Nanchang, 330052, China.
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12
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Kuo YH, Wei SH, Jiang JH, Chang YS, Liu MY, Fu SL, Huang CYF, Lin WJ. Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors. Int J Mol Sci 2021; 22:ijms222212573. [PMID: 34830455 PMCID: PMC8623086 DOI: 10.3390/ijms222212573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/18/2021] [Accepted: 11/18/2021] [Indexed: 11/16/2022] Open
Abstract
Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5–3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38β, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.
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MESH Headings
- Cell Proliferation/drug effects
- Combined Modality Therapy
- Dasatinib/pharmacology
- Drug Resistance, Neoplasm/genetics
- Fusion Proteins, bcr-abl/antagonists & inhibitors
- Fusion Proteins, bcr-abl/genetics
- Gene Knockdown Techniques
- Genetic Therapy
- Humans
- Imatinib Mesylate/pharmacology
- K562 Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Mitogen-Activated Protein Kinase 14/antagonists & inhibitors
- Mitogen-Activated Protein Kinase 14/deficiency
- Mitogen-Activated Protein Kinase 14/genetics
- Protein Kinase Inhibitors/pharmacology
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Affiliation(s)
- Yi-Hue Kuo
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.K.); (S.-H.W.); (J.-H.J.); (M.-Y.L.); (C.-Y.F.H.)
| | - Shih-Hsiang Wei
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.K.); (S.-H.W.); (J.-H.J.); (M.-Y.L.); (C.-Y.F.H.)
| | - Jie-Hau Jiang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.K.); (S.-H.W.); (J.-H.J.); (M.-Y.L.); (C.-Y.F.H.)
| | - Yueh-Shih Chang
- Hemato-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Keelung & Chang Gung University, Taoyuan City 33302, Taiwan;
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Mei-Yin Liu
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.K.); (S.-H.W.); (J.-H.J.); (M.-Y.L.); (C.-Y.F.H.)
| | - Shu-Ling Fu
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Chi-Ying F. Huang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.K.); (S.-H.W.); (J.-H.J.); (M.-Y.L.); (C.-Y.F.H.)
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Wey-Jinq Lin
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.K.); (S.-H.W.); (J.-H.J.); (M.-Y.L.); (C.-Y.F.H.)
- Correspondence: ; Tel.: +886-2-2826-7257
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13
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Schmitt C, Schulz AA, Winkelmann R, Smith K, Wild PJ, Demes M. Comparison of MET gene amplification analysis by next-generation sequencing and fluorescence in situ hybridization. Oncotarget 2021; 12:2273-2282. [PMID: 34733418 PMCID: PMC8555686 DOI: 10.18632/oncotarget.28092] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 09/28/2021] [Indexed: 11/25/2022] Open
Abstract
MET gene alterations are known to be involved in acquired resistance to epidermal growth factor receptor inhibition. MET amplifications present a potential therapeutic target in non-small cell lung cancer. Although next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) are conventionally used to assess MET amplifications, there are currently no clinically defined cut-off values for NGS, with FISH still being the gold standard. A collective of 20 formalin-fixed paraffin-embedded lung cancer tissue samples (mean age 64 years) were selected based on increased MET gene copy number (CNV) status or the presence of mutations detected by NGS (GeneReader, QIAGEN) and were further assessed by FISH (MET/CEN7, Zytomed). Of these, 17 tumor samples were MET-amplified and one patient was found to have a MET rearrangement by NGS, while two samples had no MET gene alteration. In contrast to the NGS result, FISH analysis showed only one highly amplified sample and 19 negative samples. The single highly amplified case detected by FISH was also positive by NGS with a fold change (FC) of 3.18 and a mean copy number (CNMV 10−100%) of 20.5. Therefore, for the assessment of MET amplifications using the QIAGEN NGS workflow, we suggest detecting amplified cases with an FC value of ≥ 3.0 and a CNMV 10−100% value of ≥ 20.0 by FISH. In summary, NGS allows for DNA- and RNA-based analysis of specific MET gene amplifications, point mutations or rearrangements.
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Affiliation(s)
- Christina Schmitt
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main 60590, Germany
| | - Anna-Alice Schulz
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main 60590, Germany
| | - Ria Winkelmann
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main 60590, Germany
| | - Kevin Smith
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main 60590, Germany
| | - Peter J Wild
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main 60590, Germany.,Wildlab, University Hospital Frankfurt MVZ GmbH, Frankfurt am Main 60590, Germany.,Frankfurt Institute for Advanced Studies (FIAS), Frankfurt am Main 60438, Germany
| | - Melanie Demes
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main 60590, Germany.,Wildlab, University Hospital Frankfurt MVZ GmbH, Frankfurt am Main 60590, Germany
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14
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Peters TL, Patil T, Le AT, Davies KD, Brzeskiewicz PM, Nijmeh H, Bao L, Camidge DR, Aisner DL, Doebele RC. Evolution of MET and NRAS gene amplification as acquired resistance mechanisms in EGFR mutant NSCLC. NPJ Precis Oncol 2021; 5:91. [PMID: 34642436 PMCID: PMC8511249 DOI: 10.1038/s41698-021-00231-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/22/2021] [Indexed: 12/14/2022] Open
Abstract
EGFR mutant non-small cell lung cancer patients' disease demonstrates remarkable responses to EGFR-targeted therapy, but inevitably they succumb to acquired resistance, which can be complex and difficult to treat. Analyzing acquired resistance through broad molecular testing is crucial to understanding the resistance mechanisms and developing new treatment options. We performed diverse clinical testing on a patient with successive stages of acquired resistance, first to an EGFR inhibitor with MET gene amplification and then subsequently to a combination EGFR and MET targeted therapies. A patient-derived cell line obtained at the time of disease progression was used to identify NRAS gene amplification as an additional driver of drug resistance to combination EGFR/MET therapies. Analysis of downstream signaling revealed extracellular signal-related kinase activation that could only be eliminated by trametinib treatment, while Akt activation could be modulated by various combinations of MET, EGFR, and PI3K inhibitors. The combination of an EGFR inhibitor with a MEK inhibitor was identified as a possible treatment option to overcome drug resistance related to NRAS gene amplification.
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Affiliation(s)
- T L Peters
- Department of Medicine, Division of Medical Oncology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - T Patil
- Department of Medicine, Division of Medical Oncology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - A T Le
- Department of Medicine, Division of Medical Oncology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - K D Davies
- Department of Pathology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - P M Brzeskiewicz
- Department of Pathology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - H Nijmeh
- Department of Pathology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - L Bao
- Department of Pathology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - D R Camidge
- Department of Medicine, Division of Medical Oncology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - D L Aisner
- Department of Pathology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA
| | - R C Doebele
- Department of Medicine, Division of Medical Oncology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA.
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15
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Zuo M, Yao L, Wen L, Shen J, Zhang N, Bai T, Huang Q. The expression of miRNA-216b is negatively correlated with 18F-FDG uptake in non-small cell lung cancer. World J Surg Oncol 2021; 19:262. [PMID: 34470640 PMCID: PMC8411519 DOI: 10.1186/s12957-021-02376-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 08/20/2021] [Indexed: 12/13/2022] Open
Abstract
Background This study aimed to investigate the correlation between miRNA-216b expression in patients with non-small cell lung cancer (NSCLC) and 18F-fluorodeoxyglucose (FDG) uptake by PET/CT and to explore the clinical application value of 18F-FDG PET/CT in miRNA-216b based on therapy for NSCLC. Methods Eighty patients with NSCLC and 40 healthy subjects were enrolled in our study. The SUVmax of the lesion area by PET/CT imaging was calculated. SUVmax represented the highest concentration of 18F-FDG in the lesion. The expression of miRNA-216b in the plasma and fiber bronchoscopic puncture of NSCLC patients was detected by RT qPCR. Then Pearson correlation analysis was used to analyze the correlation between miRNA-216b expression and 18F-FDG uptake in patients with different types of NSCLC. Results Compared with healthy subjects, SUVmax of early adenocarcinoma and advanced adenocarcinoma were increased. Compared with healthy subjects, SUVmax of early squamous and advanced squamous were increased. And the SUVmax content of advanced adenocarcinoma and squamous cell carcinoma was higher than that of early adenocarcinoma and squamous cell carcinoma. Compared with healthy subjects, the expression of miRNA-216b in the plasma of patients with early and advanced adenocarcinoma was reduced, and the expression of miRNA-216b in the plasma of patients with early and advanced squamous cell carcinoma was reduced. Compared with adjacent tissues, the expression of miRNA-216b in early adenocarcinoma tissues and advanced adenocarcinoma tissues was reduced, and the expression in early squamous cell carcinoma and advanced squamous cell carcinoma was reduced. Pearson correlation analysis showed a negative correlation between SUVmax and miRNA-216b (plasma and tissue) in patients with four types of NSCLC. Conclusion miRNA-216b expression was negatively correlated with 18F-FDG uptake in NSCLC. miRNA-216b could be used for the classification and staging of non-small cell lung cancer. 18F-FDG PET/CT may be used to evaluate the therapeutic response in application of miRNA-216b-based cancer treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-021-02376-2.
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Affiliation(s)
- Mingfei Zuo
- Imaging Center, The Third Affiliated Hospital of Qiqihar Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihar, 161002, Heilongjiang, China
| | - Lan Yao
- Department of Nuclear Medicine, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, 161002, Heilongjiang, China
| | - Lijuan Wen
- Imaging Center, The Third Affiliated Hospital of Qiqihar Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihar, 161002, Heilongjiang, China
| | - Jianfei Shen
- Department of Nuclear Medicine, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, 161002, Heilongjiang, China
| | - Na Zhang
- Imaging Center, The Third Affiliated Hospital of Qiqihar Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihar, 161002, Heilongjiang, China
| | - Tian Bai
- Imaging Center, The Third Affiliated Hospital of Qiqihar Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihar, 161002, Heilongjiang, China
| | - Qicheng Huang
- Imaging Center, The Third Affiliated Hospital of Qiqihar Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihar, 161002, Heilongjiang, China.
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16
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Cancer Stem Cells-Key Players in Tumor Relapse. Cancers (Basel) 2021; 13:cancers13030376. [PMID: 33498502 PMCID: PMC7864187 DOI: 10.3390/cancers13030376] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/10/2021] [Accepted: 01/18/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor relapse and treatment failure are unfortunately common events for cancer patients, thus often rendering cancer an uncurable disease. Cancer stem cells (CSCs) are a subset of cancer cells endowed with tumor-initiating and self-renewal capacity, as well as with high adaptive abilities. Altogether, these features contribute to CSC survival after one or multiple therapeutic approaches, thus leading to treatment failure and tumor progression/relapse. Thus, elucidating the molecular mechanisms associated with stemness-driven resistance is crucial for the development of more effective drugs and durable responses. This review will highlight the mechanisms exploited by CSCs to overcome different therapeutic strategies, from chemo- and radiotherapies to targeted therapies and immunotherapies, shedding light on their plasticity as an insidious trait responsible for their adaptation/escape. Finally, novel CSC-specific approaches will be described, providing evidence of their preclinical and clinical applications.
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17
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Tripathi SK, Pandey K, Rengasamy KRR, Biswal BK. Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer. Med Res Rev 2020; 40:2132-2176. [PMID: 32596830 DOI: 10.1002/med.21700] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 05/21/2020] [Accepted: 06/09/2020] [Indexed: 12/17/2022]
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have led to a substantial improvement in the prognosis of lung cancer patients by explicitly targeting the activating mutations within the EGFR. Initially, patients harboring tumors with EGFR mutations show progression-free survival and improvement in the response rates toward all-generation EGFR-TKIs; however, these agents fail to deliver the intended results in the long-term due to drug resistance. Therefore, it is necessary to recognize specific cardinal mechanisms that regulate the resistance phenomenon. Understanding the intricate mechanisms underlying EGFR-TKIs resistance in lung cancer could provide cognizance for more advanced targeted therapeutics. The present review features insights into current updates on the discrete mechanisms, including secondary or tertiary mutations, parallel and downstream signaling pathways, acquiring an epithelial-to-mesenchymal transition (EMT) signature, microRNAs (miRNAs), and epigenetic alterations, which lead to intrinsic and acquired resistance against EGFR-TKIs in lung cancer. In addition, this paper also reviews current possible strategies to overcome this issue using combination treatment of recently developed MET inhibitors, allosteric inhibitors or immunotherapies, transformation of EMT, targeting miRNAs, and epigenetic alterations in intrinsic and acquired EGFR-TKIs resistant lung cancer. In conclusion, multiple factors are responsible for intrinsic and acquired resistance to EGFR-TKIs and understanding of the detailed molecular mechanisms, and recent advancements in pharmacological studies are needed to develop new strategies to overcome intrinsic and acquired EGFR-TKIs resistance in lung cancer.
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Affiliation(s)
- Surya K Tripathi
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
| | - Kamal Pandey
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
| | - Kannan R R Rengasamy
- Department of Bioresources and Food Science, Konkuk University, Seoul, South Korea
| | - Bijesh K Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
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18
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Overbeck TR, Cron DA, Schmitz K, Rittmeyer A, Körber W, Hugo S, Schnalke J, Lukat L, Hugo T, Hinterthaner M, Reuter-Jessen K, Rosenthal T, Moecks J, Bleckmann A, Schildhaus HU. Top-level MET gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis. Transl Lung Cancer Res 2020; 9:603-616. [PMID: 32676323 PMCID: PMC7354108 DOI: 10.21037/tlcr-19-339] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background MET amplifications occur in human tumors, including non-small cell lung cancer (NSCLC). MET inhibitors have demonstrated some clinical activity in MET amplified NSCLC, presumably with a gene dose effect. However, the definition of MET positivity or MET amplification as a potential oncogenic driver is still under debate. In this study, we aimed to establish the molecular subgroup of NSCLC with the highest unequivocal MET amplification level and to describe the prevalence, and histologic and clinical phenotype of this subgroup. Methods A total of 373 unselected patients with NSCLC were consecutively tested for MET gene copy number (GCN) by FISH. Mean GCN, MET/CEN7 ratio and other FISH parameters were identified and correlated with morphological and molecular pathological characteristics of the tumors as well as with clinical data. Results Based on the variability of obtained data a top-level category of MET amplification was newly defined (>90th percentile of average GCN; ≥10 MET gene copies per tumor cell). This criterion was fulfilled in 2% of analyzed tumors. These tumors were exclusively poorly differentiated adenocarcinomas with a predominant solid subtype and pleomorphic features. Rarely, co-alterations were detected (KRAS mutation or MET exon 14 skipping mutation). In this top-level group, there were no EGFR mutations or ALK or ROS1 alterations. The most important clinical feature was a significantly shortened overall survival (HR 3.61; median OS 8.2 vs. 23.6 months). Worse prognosis did not depend on initial stage or treatment. Conclusions The newly defined top-level category of MET amplification in NSCLC defines a specific subgroup of pulmonary adenocarcinoma with adverse prognosis and characteristic morphological features. Lower levels of MET gene copy number seem to have probably no specific value as a prognostic or predictive biomarker.
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Affiliation(s)
- Tobias Raphael Overbeck
- Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.,Lungentumorzentrum Universität Göttingen and Göttingen Comprehensive Cancer Center (G-CCC), Göttingen, Germany
| | - Dana Alina Cron
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Katja Schmitz
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.,Innpath GmbH, Innsbruck, Austria
| | - Achim Rittmeyer
- Lungentumorzentrum Universität Göttingen and Göttingen Comprehensive Cancer Center (G-CCC), Göttingen, Germany.,Lungenfachklinik Immenhausen, Immenhausen, Germany
| | - Wolfgang Körber
- Lungentumorzentrum Universität Göttingen and Göttingen Comprehensive Cancer Center (G-CCC), Göttingen, Germany.,Abteilung Pneumologie, Beatmungsmedizin und Schlaflabor, Evangelisches Krankenhaus Weende, Göttingen, Germany
| | - Sara Hugo
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Juliane Schnalke
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Laura Lukat
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Tabea Hugo
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Marc Hinterthaner
- Lungentumorzentrum Universität Göttingen and Göttingen Comprehensive Cancer Center (G-CCC), Göttingen, Germany.,Department of Heart, Thoracic and Vascular Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Kirsten Reuter-Jessen
- Lungentumorzentrum Universität Göttingen and Göttingen Comprehensive Cancer Center (G-CCC), Göttingen, Germany.,Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Tessa Rosenthal
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | | | - Annalen Bleckmann
- Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.,Department of Medicine A, University Hospital Muenster, Muenster, Germany
| | - Hans-Ulrich Schildhaus
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.,Institute of Pathology, University Hospital Essen, Essen, Germany.,West German Cancer Center (WTZ), Essen, Germany
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Huang W, Wu Y, Cheng D, He Z. Mechanism of epithelial‑mesenchymal transition inhibited by miR‑203 in non‑small cell lung cancer. Oncol Rep 2019; 43:437-446. [PMID: 31894278 PMCID: PMC6967097 DOI: 10.3892/or.2019.7433] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 10/25/2019] [Indexed: 01/05/2023] Open
Abstract
The aim of the present study was to investigate whether miR-203 can inhibit transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT), and the migration and invasion ability of non-small cell lung cancer (NSCLC) cells by targeting SMAD3. In the present study, the expression levels of miR-203, SMAD3 mRNA and protein in NSCLC tissues were examined, as well as their corresponding paracancerous samples. The miR-203 mimics and miR-203 inhibitor were transfected into the H226 cell line. RT-qPCR was used to assess the expression levels of E-cadherin, Snail, N-cadherin and vimentin mRNA, and western blotting was performed to detect the expression levels of p-SMAD2, SMAD2, p-SMAD3, SMAD3 and SMAD4. The cell migration and invasion abilities were detected by Transwell assays. The target site of SMAD3 was predicted by the combined action between miR-203 and dual luciferase. The results revealed that the RNA levels of miR-203, compared with paracancerous tissues, were decreased in NSCLC tissues, while SMAD3 mRNA and protein levels were upregulated, and miR-203 inhibited SMAD3 expression. Induction of TGF-β led to decreased E-cadherin mRNA levels, upregulation of Snail, N-cadherin and vimentin mRNA levels (P<0.05), and significant increase in cell migration and invasion, whereas transfection of miR-203 mimics reversed the aforementioned results (P<0.05). Conversely, miR-203 inhibitor could further aggravate the aforementioned results (P<0.05). Western blot results revealed that transfection of miR-203 mimics significantly reduced the protein expression of SMAD3 and p-SMAD3 (P<0.05). Furthermore, the results of the Dual-Luciferase assay revealed that miR-203 inhibited SMAD3 expression by interacting with specific regions of its 3′-UTR. Overall, a novel mechanism is revealed, in which, miR-203 can inhibit SMAD3 by interacting with specific regions of the 3′-UTR of SMAD3, thereby restraining TGF-β-induced EMT progression and migration and invasion of NSCLC cells.
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Affiliation(s)
- Weicong Huang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yuanbo Wu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Dezhi Cheng
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhifeng He
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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20
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Singh PK, Chaudhari D, Jain S, Silakari O. Structure based designing of triazolopyrimidone-based reversible inhibitors for kinases involved in NSCLC. Bioorg Med Chem Lett 2019; 29:1565-1571. [PMID: 31078412 DOI: 10.1016/j.bmcl.2019.05.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/24/2019] [Accepted: 05/05/2019] [Indexed: 10/26/2022]
Abstract
Secondary acquired mutant EGFR (L858R-T790M) overexpressed NSCLC forms one of the prevalent form of resistant NSCLC. Another subset of resistant NSCLC includes amplified cMET in mutant EGFR derived tumours. Thus, in continuation to our previous work on these two major targets of resistant NSCLC, i.e., EGFR (L858R-T790M) and cMET, we are hereby reporting reversible inhibitors of these kinases. Out of 11 lead molecules reported in our previous study, we selected triazolo-pyrimidone (BAS 09867482) scaffold for further development of small molecule dual and reversible inhibitors. Analogues of lead with different substituents on the side ring were sketched and docked in both the target kinases, followed by molecular dynamic simulations. Analogues maintaining hydrophobic interaction with M790 in secondary acquired mutant EGFR (L858R-T790M) were selected and duly synthesized. In vitro biochemical evaluation of these molecules against EGFR (L858R-T790M) and cMET kinase, along with EGFR (L858R) kinase disclosed that three molecules were having significant dual kinase inhibitory potential with IC50 values well below 100 nM. Further, in vitro anti-proliferative assay against three cell lines (A549, A431 and H460) was performed. Out of all, two compounds were having significant potency against these cell lines.
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Affiliation(s)
- Pankaj Kumar Singh
- Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India
| | - Dasharath Chaudhari
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, NIPER, SAS Nagar, Mohali, Punjab, India
| | - Sanyog Jain
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, NIPER, SAS Nagar, Mohali, Punjab, India
| | - Om Silakari
- Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
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21
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Kumar Singh P, Silakari O. In silico guided development of imine-based inhibitors for resistance-deriving kinases. J Biomol Struct Dyn 2018; 37:2593-2599. [PMID: 30047303 DOI: 10.1080/07391102.2018.1491893] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Two major mechanisms involved in resistant NSCLC (non-small cell lung cancer) include secondary acquired mutation in EGFR (epidermal growth factor receptor), that is, EGFR T790M and amplification of c-MET (hepatocyte growth factor receptor). Thus, already established pharmacophore models of EGFR T790M and c-MET were employed to filter-out an in-house database. Further fitness score led to the selection of imino-pyrimidine scaffold. Followed by sketching of imino-pyrimidine derivatives having varied aryl substitutions, which were then docked and subjected to molecular dynamic simulations, to study the orientations and conformations of the designed molecules in the catalytic domain. Molecules with hydrophobic interaction with mutant residue M790 were selected. Finally, MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) calculations were performed, to study the effect of substitutions on the binding affinity of the double mutant EGFR towards these small molecules. Finally, the designed compounds were synthesized and evaluated for their kinase inhibitory potential using in-vitro experiments. Two compounds were found to possess sub-micromolar range inhibitory potential against EGFR (T790M), while one of the compound showed significant selective inhibitory potential against c-MET. Additionally, one compound was found to possess significant dual inhibitory potential against these target kinases. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Pankaj Kumar Singh
- a Molecular Modelling Lab (MML) , Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , Punjab , India
| | - Om Silakari
- a Molecular Modelling Lab (MML) , Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , Punjab , India
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22
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Wu Y, Fan Q, Zeng F, Zhu J, Chen J, Fan D, Li X, Duan W, Guo Q, Cao Z, Briley-Saebo K, Li C, Tao X. Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling. NANO LETTERS 2018; 18:5488-5498. [PMID: 30067910 DOI: 10.1021/acs.nanolett.8b01879] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Malignant gliomas are the most common primary brain tumors and are associated with aggressive growth, high morbidity, and mortality. Aberrant mesenchymal-epithelial transition factor (MET) activation occurs in approximately 30% of glioma patients and correlates with poor prognosis, elevated invasion, and increased drug resistance. Therefore, MET has emerged as an attractive target for glioma therapy. In this study, we developed a novel nanoinhibitor by conjugating MET-targeting cMBP peptides on the G4 dendrimer. Compared to the binding affinity of the free peptide ( KD = 3.96 × 10-7 M), the binding affinity of the nanoinhibitor to MET increased 3 orders of magnitude to 1.32 × 10-10 M. This nanoinhibitor efficiently reduced the proliferation and invasion of human glioblastoma U87MG cells in vitro by blocking MET signaling with remarkably attenuated levels of phosphorylated MET ( pMET) and its downstream signaling proteins, such as pAKT and pERK1/2. Although no obvious therapeutic effect was observed after treatment with free cBMP peptide, in vivo T2-weighted magnetic resonance imaging (MRI) showed a significant delay in tumor growth after intravenous injection of the nanoinhibitor. The medium survival in mouse models was extended by 59%, which is similar to the effects of PF-04217903, a small molecule MET inhibitor currently in clinical trials. Immunoblotting studies of tumor homogenate verified that the nanoinhibitor restrained glioma growth by blocking MET downstream signaling. pMET and its downstream proteins pAKT and pERK1/2, which are involved in the survival and invasion of cancer cells, decreased in the nanoinhibitor-treated group by 44.2%, 62.2%, and 32.3%, respectively, compared with those in the control group. In summary, we developed a peptide-functionalized MET nanoinhibitor that showed extremely high binding affinity to MET and effectively inhibited glioma growth by blocking MET downstream signaling. To the best of our knowledge, this is the first report of therapeutic inhibition of glioma growth by blocking MET signaling with a novel nanoinhibitor. Compared to antibodies and chemical inhibitors in clinical trials, the nanoinhibitor blocks MET signaling and provides a new approach for the treatment of glioma with the advantages of high efficiency, affordability, and, most importantly, potentially reduced drug resistance.
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Affiliation(s)
- Yingwei Wu
- Department of Radiology, Shanghai Ninth People's Hospital , Shanghai Jiao Tong University , Shanghai 200011 , China
| | - Qi Fan
- Department of Radiology, Shanghai Ninth People's Hospital , Shanghai Jiao Tong University , Shanghai 200011 , China
| | - Feng Zeng
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China
| | - Jinyu Zhu
- Department of Radiology, Shanghai Ninth People's Hospital , Shanghai Jiao Tong University , Shanghai 200011 , China
| | - Jian Chen
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China
| | - Dandan Fan
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China
| | - Xinwei Li
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China
| | - Wenjia Duan
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China
| | - Qinghua Guo
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China
| | - Zhonglian Cao
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China
| | - Karen Briley-Saebo
- Department of Radiology , the Ohio State University Wexner Medical Center, Wright Center of Innovation in Biomedical Imaging , Columbus , Ohio 43210 , United States
| | - Cong Li
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China
| | - Xiaofeng Tao
- Department of Radiology, Shanghai Ninth People's Hospital , Shanghai Jiao Tong University , Shanghai 200011 , China
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23
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Singh PK, Silakari O. Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-MET. Bioorg Chem 2018; 79:163-170. [DOI: 10.1016/j.bioorg.2018.04.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 04/04/2018] [Accepted: 04/06/2018] [Indexed: 01/17/2023]
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24
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Han Z, Xiao Y, Wang K, Yan J, Xiao Z, Fang F, Jin Z, Liu Y, Sun X, Shen B. Development of a SPECT Tracer to Image c-Met Expression in a Xenograft Model of Non–Small Cell Lung Cancer. J Nucl Med 2018; 59:1686-1691. [PMID: 29777004 DOI: 10.2967/jnumed.117.206730] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 05/08/2018] [Indexed: 12/18/2022] Open
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25
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Liu S, Dong H, Dai H, Liu D, Wang Z. MicroRNA-216b regulated proliferation and invasion of non-small cell lung cancer by targeting SOX9. Oncol Lett 2018; 15:10077-10083. [PMID: 29928377 DOI: 10.3892/ol.2018.8573] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 12/21/2016] [Indexed: 12/21/2022] Open
Abstract
Micro (mi)RNAs are small, evolutionarily conserved and endogenous noncoding RNA molecules between 19 and 24 nucleotides in length. The potential roles of miRNAs in the carcinogenesis and progression of non-small cell lung cancer (NSCLC) have been studied previously. In the present study, it was revealed that miRNA-216b (miR-216b) expression was lower in NSCLC tissue and cell lines compared with that in adjacent healthy lung tissue samples and the normal bronchial epithelial 16HBE cell line, respectively. The ectopic expression of miR-216b inhibited the proliferation and invasion of NSCLC cells in vitro. SRY-Box 9 (SOX9) was identified as a direct target of miR-216b in NSCLC. In addition, SOX9 small interfering RNA was able to mimic the effects of miR-216b overexpression on cell proliferation and invasion in NSCLC. Therefore, the data reported in the present study demonstrate that miR-216b is an important tumor suppressor in NSCLC. These data may contribute to the understanding of the molecular mechanism underlying the carcinogenesis and progression of NSCLC, and provide novel therapies for patients with NSCLC.
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Affiliation(s)
- Sida Liu
- Department of Thoracic Surgery, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Han Dong
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hui Dai
- Department of Tumor and Blood Disease, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
| | - Danwei Liu
- Department of Infections, People's Hospital of Jilin Province, Changchun, Jilin 130021, P.R. China
| | - Zhihao Wang
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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26
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Bronte G, Bravaccini S, Bronte E, Burgio MA, Rolfo C, Delmonte A, Crinò L. Epithelial-to-mesenchymal transition in the context of epidermal growth factor receptor inhibition in non-small-cell lung cancer. Biol Rev Camb Philos Soc 2018; 93:1735-1746. [PMID: 29671943 DOI: 10.1111/brv.12416] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 03/20/2018] [Accepted: 03/23/2018] [Indexed: 12/12/2022]
Abstract
The identification of oncogenic driver mutations in non-small-cell lung cancer (NSCLC) has led to the development of targeted drugs. Tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR) target lung tumours bearing EGFR-activating mutations. This new therapeutic strategy has greatly improved tumour response rates. However, drug resistance invariably occurs during TKI-based treatment. Epithelial-to-mesenchymal transition (EMT) is one of the resistance mechanisms identified in EGFR-mutated NSCLC treated with TKIs. In this review we gather together the most important findings on this phenomenon in relation to cancer stem cells and cancer epigenetics. We also outline the correlation between the effects of stromal factors from the microenvironment, the transcription factors activated, the epigenetic changes in chromatin, and the evolution of cellular behaviour. Notably, EMT has already been shown to be the link between benign lung diseases such as chronic obstructive pulmonary disease and lung carcinogenesis. The various mechanisms of acquired resistance to EGFR-TKIs are also briefly described to provide background information on EMT. Our extensive review of the scientific literature serves to highlight the cellular and molecular events that lead to the onset of EMT in NSCLC cells treated with EGFR-TKIs. Finally, we put forward a hypothesis to explain why, in some cases, EMT rather than other known mechanisms is involved in resistance to TKIs.
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Affiliation(s)
- Giuseppe Bronte
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy
| | - Sara Bravaccini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Enrico Bronte
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Marco Angelo Burgio
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy
| | - Christian Rolfo
- Phase I Early Clinical Trials Unit, Department of Oncology, Universitair Ziekenhuis Antwerpen, Edegem, Belgium
| | - Angelo Delmonte
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy
| | - Lucio Crinò
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy
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27
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Hussmann D, Madsen AT, Jakobsen KR, Luo Y, Sorensen BS, Nielsen AL. IGF1R depletion facilitates MET-amplification as mechanism of acquired resistance to erlotinib in HCC827 NSCLC cells. Oncotarget 2018; 8:33300-33315. [PMID: 28418902 PMCID: PMC5464869 DOI: 10.18632/oncotarget.16350] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/1969] [Accepted: 02/22/2017] [Indexed: 01/16/2023] Open
Abstract
EGFR-mutated non-small cell lung cancer patients experience relapse within 1-2 years of treatment with EGFR-inhibitors, such as erlotinib. Multiple resistance mechanisms have been identified including secondary EGFR-mutations, MET-amplification, and epithelial-mesenchymal transition (EMT). Previous studies have indicated a role of Insulin-like growth factor 1 receptor (IGF1R) in acquired resistance to EGFR-directed drugs as well as in EMT. In the present study, we have investigated the involvement of IGF1R in acquired high-dose erlotinib resistance in the EGFR-mutated lung adenocarcinoma cell line HCC827. We observed that IGF1R was upregulated in the immediate response to erlotinib and hyperactivated in erlotinib resistant HCC827 cells. Resistant cells additionally acquired features of EMT, whereas MET-amplification and secondary EGFR-mutations were absent. Using CRISPR/Cas9, we generated a HCC827(IGFR1-/-) cell line and subsequently investigated resistance development in response to high-dose erlotinib. Interestingly, HCC827(IGFR1-/-) cells were now observed to specifically amplify the MET gene. Additionally, we observed a reduced level of mesenchymal markers in HCC827(IGFR1-/-) indicating an intrinsic enhanced epithelial signature compared to HCC827 cells. In conclusion, our data show that IGF1R have an important role in defining selected resistance mechanisms in response to high doses of erlotinib.
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Affiliation(s)
- Dianna Hussmann
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Anne Tranberg Madsen
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Kristine Raaby Jakobsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Yonglun Luo
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Boe Sandahl Sorensen
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
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28
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González-Larriba JL, Lázaro-Quintela M, Cobo M, Dómine M, Majem M, García-Campelo R. Clinical management of epidermal growth factor receptor mutation-positive non-small cell lung cancer patients after progression on previous epidermal growth factor receptor tyrosine kinase inhibitors: the necessity of repeated molecular analysis. Transl Lung Cancer Res 2017; 6:S21-S34. [PMID: 29299405 PMCID: PMC5750154 DOI: 10.21037/tlcr.2017.10.03] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 09/29/2017] [Indexed: 12/17/2022]
Abstract
One of the most important advances in the treatment of non-small cell lung cancer (NSCLC) has been the identification of molecular alterations vulnerable to targeted inhibition, such as mutations in the epidermal growth factor receptor (EGFR) gene. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are targeted agents used to treat EGFR mutation-positive advanced NSCLC showing significant improvements in terms of response rate (RR) and progression-free survival (PFS) compared to conventional chemotherapy. However, all patients eventually develop resistance to first-line EGFR-TKIs. The most common mechanism of acquired resistance is the secondary acquisition of a single missense mutation within exon 20 in the EGFR gene, known as the T790M mutation (49-60%). New agents targeting the T790M mutation have undergone clinical development, and among these, osimertinib has shown significant activity in relapsing EGFR mutation positive patients harbouring the T790M mutation. Although precision medicine is a reality for NSCLC, obtaining relevant tissue for repeated molecular analysis from these patients remains a challenge. In this article, a group of experts from the Spanish Society of Medical Oncology (SEOM) and the Spanish Lung Cancer Group (GECP) evaluated the role of rebiopsy and the potential application of plasma-testing methodologies in advanced EGFR mutation patients progressing after EGFR-TKI.
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Affiliation(s)
| | | | - Manuel Cobo
- Department of Medical Oncology, Málaga University Hospital, General and Virgen de la Victoria, IBIMA, Málaga, Spain
| | - Manuel Dómine
- Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Margarita Majem
- Department of Medical Oncology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
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29
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Abstract
MET encodes a receptor tyrosine kinase c-MET for hepatocyte growth factor (HGF). The specific combination of c-MET and HGF activates downstream signaling pathways to trigger cell migration, proliferation, and angiogenesis. MET exon 14 alterations and MET gene amplification play a critical role in the origin of cancer. Several monoclonal antibodies and small-molecule inhibitors of c-MET have been evaluated in clinical trials. In patients with advanced non-small cell lung cancer, cabozantinib and crizotinib showed clear efficacy with a generally tolerable adverse events profile. In gastrointestinal cancers, most phase III trials of MET inhibitors showed negative results. In hepatocellular carcinoma, based on the encouraging results of some phase II studies, a series of phase III trials are currently recruiting patients to access the efficacy and safety of MET inhibitors.
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Affiliation(s)
- Hong-Nan Mo
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Peng Liu
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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30
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Chalela R, Curull V, Enríquez C, Pijuan L, Bellosillo B, Gea J. Lung adenocarcinoma: from molecular basis to genome-guided therapy and immunotherapy. J Thorac Dis 2017; 9:2142-2158. [PMID: 28840016 PMCID: PMC5542927 DOI: 10.21037/jtd.2017.06.20] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 05/21/2017] [Indexed: 12/14/2022]
Abstract
Although adenocarcinoma (ADC) is the most frequent lung cancer, its diagnosis is often late, when the local invasion is important and/or the metastases have already appeared. Therefore, the mortality at 5 years is still very high, ranging from 51% to 99%, depending on the stage. The implementation of different molecular techniques has allowed genomic studies even in relatively small histological samples such as obtained with non-invasive or minimally invasive techniques, facilitating a better phenotyping of lung ADC. Thus, current classification differentiates between preinvasive lesions (atypical adenomatous hyperplasia and in situ ADC), minimally invasive ADC (MIA) and invasive ADC. 'Field cancerization' is a concept that refers to progressive loco-regional changes occurring in tissues exposed to carcinogens, due to the interaction of the latter with a predisposing genetic background and an appropriate tissue microenvironment. Somatic genetic alterations, including mutations but also other changes, are necessary for oncogenesis, being especially frequent in lung ADC. Changes in the epidermal growth factor receptor (EGFR) gene, Kirsten rat sarcoma viral oncogene (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), gene encoding neurofibromin (NF1), anaplastic lymphoma kinase (ALK) and ROS1 are the main genes that suffer alterations in the tumors of patients with ADC. Molecular profiling of these tumors allows more targeted treatments through two distinct strategies, genome-guided therapy and immunotherapy. The former, targets the aberrant pathways secondary to the genomic alteration, whereas the latter may be based on the administration of antibodies [such as those against cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the programmed cell death ligand 1/protein 1 pathway (PD-L1/PD-1)] or the stimulation of the patient's own immune system to produce a specific response. These strategies are obtaining better results in selected ADC patients.
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Affiliation(s)
- Roberto Chalela
- Respiratory Medicine Department, Hospital del Mar; and CIBER de Enfermedades Respiratorias (CIBERES), ISCIII, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Víctor Curull
- Respiratory Medicine Department, Hospital del Mar; and CIBER de Enfermedades Respiratorias (CIBERES), ISCIII, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Lara Pijuan
- Department of Pathology, Hospital del Mar, Barcelona, Spain
| | - Beatriz Bellosillo
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
- Department of Pathology, Hospital del Mar, Barcelona, Spain
| | - Joaquim Gea
- Respiratory Medicine Department, Hospital del Mar; and CIBER de Enfermedades Respiratorias (CIBERES), ISCIII, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
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31
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Nakamura T, Watanabe N, Sato A, Komiya K, Umeguchi H, Hosomi T, Hirai M, Sueoka E, Kimura S, Sueoka-Aragane N. Plasma T790M and HGF as potential predictive markers for EGFR-TKI re-challenge. Oncol Lett 2017; 13:4939-4946. [PMID: 28588734 DOI: 10.3892/ol.2017.6085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 02/23/2017] [Indexed: 12/15/2022] Open
Abstract
Re-challenge with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has been suggested to potentially improve survival in certain populations of patients with advanced lung cancer, but predictive markers for the success of EGFR-TKI re-challenge have not been identified. The present study analyzed 16 re-challenges with EGFR-TKI undertaken in 12 patients with lung adenocarcinoma by investigating T790M and hepatocyte growth factor (HGF) in plasma coupled with clinical characteristics. EGFR mutations in plasma DNA were detected using the wild inhibiting PCR and quenched probe system for exon 19 deletions, and T790M and L858R were detected using the mutation-biased PCR and quenched probe system. HGF levels in the plasma were measured by enzyme-linked immunosorbent assay, and the ratio of HGF levels prior to re-challenge to those prior to the previous EGFR-TKI treatment was calculated. Two re-challenges demonstrated partial response, six remained as stable disease and eight had progressive disease (PD). A total of 4 of the 5 patients with a history of T790M positivity based on plasma DNA levels had PD. A total of 7 of the 8 patients who had ≥1.5-fold elevation of HGF prior to re-challenge with EGFR-TKI suffered PD. Elevation of the HGF ratio to ≥1.5 was significantly associated with poor response to EGFR-TKI re-challenge. Having no history of T790M and an HGF ratio <1.5 was significantly associated with a positive response to EGFR-TKI re-challenge. A combination of T790M detection and HGF quantification using plasma is a potentially useful assay system for predicting the effect of EGFR-TKI re-challenge. Future prospective studies are required to confirm the predictive validity of these markers.
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Affiliation(s)
- Tomomi Nakamura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Naomi Watanabe
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Akemi Sato
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Kazutoshi Komiya
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Hitomi Umeguchi
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | | | | | - Eisaburo Sueoka
- Department of Laboratory Medicine, Saga University Hospital, Saga 849-8501, Japan
| | - Shinya Kimura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Naoko Sueoka-Aragane
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
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Abstract
The advent of genomics has led to the identification of specific "driver" mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance.
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Yang Q, Wang P, Cui J, Wang W, Chen Y, Zhang T. Panax notoginseng saponins attenuate lung cancer growth in part through modulating the level of Met/miR-222 axis. JOURNAL OF ETHNOPHARMACOLOGY 2016; 193:255-265. [PMID: 27566197 DOI: 10.1016/j.jep.2016.08.040] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 08/19/2016] [Accepted: 08/22/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Panax notoginseng saponins (PNS) are the major chemical constituents of Panax notoginseng (Burkill) F.H. Chen (Araliaceae), a medicinal herb extensively used in China for the treatment of various diseases including cancer. PNS have been reported to contribute to the therapeutic effects of Panax notoginseng in disease conditions including lung cancer. AIM OF THE STUDY The current study aims to further understand the molecular mechanisms implicated in the pharmacological activities of PNS in attenuating lung cancer growth. MATERIALS AND METHODS Lewis lung carcinoma (LLC) cell line was employed and the impact of PNS treatment on the viability of LLC cells was first examined in vitro. The tumor-suppressive effect of PNS was further validated in vivo by assessing the tumor growth in BALB/c mice inoculated with LLC cells. Whole genome microarray and real-time PCR analyses were performed to examine and verify altered expression of genes associated with PNS treatment. Real-time PCR and western blotting analyses were also carried out to investigate the implication of microRNA (miRNA)-mediated gene expression regulation in the anti-tumor activity of PNS. RESULTS PNS treatment resulted in selective impairment of the survival of LLC cells. Furthermore, PNS treatment led to attenuated growth of tumors derived from inoculated LLC cells in mice. Bioinformatic analyses of gene expression profiles revealed that multiple pathways associated with tumorigenesis were significantly modulated by PNS treatment in vivo. The expression of an array of genes promoting tumorigenesis and progression including Hgf, Met, Notch3, Scd1, Epas1, Col1a1, Raf1, Braf1 and CDK6 was significantly decreased by PNS treatment, whereas the expression of tumor suppressive Rxrg was significantly increased as a result of PNS treatment. The level of miR-222, a miRNA regulated by Met, was significantly decreased by PNS treatment. The expression of tumor suppressor p27 and PTEN, miR-222 target genes, was significantly increased by PNS treatment. CONCLUSION Out work here presented novel evidence demonstrating that multiple mechanisms were implicated in the anti-tumor effects of PNS in lung cancer models. Particularly, PNS treatment significantly modulated the level of Met/miR-222 axis in LLC cells. Increased understanding of the anti-tumor mechanisms of PNS may provide further experimental evidence to help optimize the therapeutic modalities for the treatment of lung cancer and other types of cancer.
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Affiliation(s)
- Qinbo Yang
- Clinical Research Institute of Integrative Medicine and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Peiwei Wang
- Clinical Research Institute of Integrative Medicine and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Jingang Cui
- Clinical Research Institute of Integrative Medicine and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Wenjian Wang
- Clinical Research Institute of Integrative Medicine and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yu Chen
- Clinical Research Institute of Integrative Medicine and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
| | - Teng Zhang
- Clinical Research Institute of Integrative Medicine and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
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Feng C, Liu X, Li X, Guo F, Huang C, Qin Q, Wang Y. Zoledronic acid increases the antitumor effect of gefitinib treatment for non-small cell lung cancer with EGFR mutations. Oncol Rep 2016; 35:3460-70. [PMID: 27109760 DOI: 10.3892/or.2016.4741] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 10/31/2015] [Indexed: 02/05/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations and bone metastases are often concurrently administered tyrosine kinase inhibitors (TKIs) and bisphosphonates. Yet, the effects and mechanisms of these agents are unclear. In the present study, we aimed to ascertain whether zoledronic acid (ZA) increases the antitumor effects of gefitinib treatment on NSCLC with EGFR mutations and the related mechanisms of action. The effects of ZA and gefitinib on NSCLC tumor cells with EGFR mutations (HCC827, HCC827 GR and H1975) in regards to proliferation, apoptosis, cell cycle and signaling pathways were detected. ZA increased the antitumor effects of gefitinib on NSCLC with EGFR activating mutations and TKI resistance in vitro. Gefitinib caused cell cycle arrest in the G0/G1 phase, ZA induced S phase accumulation and the effect of the combined treatment was neutralization. Combined treatment obviously inhibited STAT3 and/or p‑STAT3 protein expression compared with treatment with each single drug in vitro and in vivo, and it also significantly inhibited TKI resistance NSCLC tumor growth in vivo. In conclusion, ZA increased the antitumor effects of gefitinib on NSCLC with EGFR activating mutations and TKI resistance by regulating the cell cycle, inducing caspase-3 expression and inhibiting STAT3 expression.
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Affiliation(s)
- Chengjun Feng
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaoke Liu
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaoyu Li
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fuchun Guo
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Chuying Huang
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qing Qin
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yongsheng Wang
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Qu MH, Han C, Srivastava AK, Cui T, Zou N, Gao ZQ, Wang QE. miR-93 promotes TGF-β-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells. Tumour Biol 2016; 37:5645-51. [PMID: 26581907 PMCID: PMC6528179 DOI: 10.1007/s13277-015-4328-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 10/26/2015] [Indexed: 12/18/2022] Open
Abstract
The level of microRNA-93 (miR-93) in tumors has been recently reported to be negatively correlated with survival of lung cancer patients. Considering that the most devastating aspect of lung cancer is metastasis, which can be promoted by transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal transition (EMT), we sought to determine whether miR-93 is involved in this process. Here, we report that a previously unidentified target of miR-93, neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L), is able to mediate TGF-β-mediated EMT in lung cancer cells. miR-93 binds directly to the 3'-UTR of the NEDD4L messenger RNA (mRNA), leading to a downregulation of NEDD4L expression at the protein level. We next demonstrated that the downregulation of NEDD4L enhanced, while overexpression of NEDD4L reduced TGF-β signaling, reflected by increased phosphorylation of SMAD2 in the lung cancer cell line after TGF-β treatment. Furthermore, overexpression of miR-93 in lung cancer cells promoted TGF-β-induced EMT through downregulation of NEDD4L. The analysis of publicly available gene expression array datasets indicates that low NEDD4L expression correlates with poor outcomes among patients with lung cancer, further supporting the oncogenic role of miR-93 in lung tumorigenesis and metastasis.
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Affiliation(s)
- Mei-Hua Qu
- Department of Pharmacology, Key Lab of Applied Pharmacology in Universities of Shandong, Weifang Medical University, 7166 Baotong West St, Weifang, 261053, Shandong, China.
- Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA.
| | - Chunhua Han
- Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA
| | - Amit Kumar Srivastava
- Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA
| | - Tiantian Cui
- Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA
| | - Ning Zou
- Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA
| | - Zhi-Qin Gao
- Department of Pharmacology, Key Lab of Applied Pharmacology in Universities of Shandong, Weifang Medical University, 7166 Baotong West St, Weifang, 261053, Shandong, China
| | - Qi-En Wang
- Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA.
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Zhang T, Boominathan R, Foulk B, Rao C, Kemeny G, Strickler JH, Abbruzzese JL, Harrison MR, Hsu DS, Healy P, Li J, Pi C, Prendergast KM, Hobbs C, Gemberling S, George DJ, Hurwitz HI, Connelly M, Garcia-Blanco MA, Armstrong AJ. Development of a Novel c-MET-Based CTC Detection Platform. Mol Cancer Res 2016; 14:539-47. [PMID: 26951228 DOI: 10.1158/1541-7786.mcr-16-0011] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 02/25/2016] [Indexed: 11/16/2022]
Abstract
UNLABELLED Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers. IMPLICATIONS This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. ©2016 AACR.
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Affiliation(s)
- Tian Zhang
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Rengasamy Boominathan
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Brad Foulk
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Chandra Rao
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Gabor Kemeny
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - John H Strickler
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - James L Abbruzzese
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Michael R Harrison
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - David S Hsu
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Patrick Healy
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Jing Li
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Cinthia Pi
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Katherine M Prendergast
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Carey Hobbs
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Sarah Gemberling
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Daniel J George
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Herbert I Hurwitz
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Mark Connelly
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Mariano A Garcia-Blanco
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Andrew J Armstrong
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC.
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Abstract
Lung cancer is the leading cause of cancer-related deaths in United States, accounting for more than one-fourth of the deaths annually. Although comparatively rare and relatively less studied, genetic abnormalities other than epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and Kirsten rat sarcoma (KRAS) mutations account for significant proportion of the driver mutations identified thus far. The targeted agents against B-rapidly accelerated fibrosarcoma (BRAF) V600E mutation, MNNG-HOS transforming gene (MET) pathway, ROS1 rearrangement, rearranged during transfection (RET) rearrangement, and HER2 pathways offer promising therapeutic options. Recruiting patients with these rarer mutations to well-designed, large multicenter trials to further validate the use of targeted agents remains a challenge. The clinical data and ongoing trials with these agents are reviewed in this article.
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Affiliation(s)
- Nabin Khanal
- a Department of Internal Medicine , Creighton University Medical Center , Omaha , NE , USA
| | - Apar Kishor Ganti
- b Division of Oncology-Hematology, Department of Internal Medicine , VA-Nebraska Western Iowa Health Care System , Omaha , NE , USA.,c Division of Oncology-Hematology, Department of Internal Medicine , University of Nebraska Medical Center , Omaha , NE , USA
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38
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Patterson SE, Liu R, Statz CM, Durkin D, Lakshminarayana A, Mockus SM. The clinical trial landscape in oncology and connectivity of somatic mutational profiles to targeted therapies. Hum Genomics 2016; 10:4. [PMID: 26772741 PMCID: PMC4715272 DOI: 10.1186/s40246-016-0061-7] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 01/10/2016] [Indexed: 12/24/2022] Open
Abstract
Background Precision medicine in oncology relies on rapid associations between patient-specific variations and targeted therapeutic efficacy. Due to the advancement of genomic analysis, a vast literature characterizing cancer-associated molecular aberrations and relative therapeutic relevance has been published. However, data are not uniformly reported or readily available, and accessing relevant information in a clinically acceptable time-frame is a daunting proposition, hampering connections between patients and appropriate therapeutic options. One important therapeutic avenue for oncology patients is through clinical trials. Accordingly, a global view into the availability of targeted clinical trials would provide insight into strengths and weaknesses and potentially enable research focus. However, data regarding the landscape of clinical trials in oncology is not readily available, and as a result, a comprehensive understanding of clinical trial availability is difficult. Results To support clinical decision-making, we have developed a data loader and mapper that connects sequence information from oncology patients to data stored in an in-house database, the JAX Clinical Knowledgebase (JAX-CKB), which can be queried readily to access comprehensive data for clinical reporting via customized reporting queries. JAX-CKB functions as a repository to house expertly curated clinically relevant data surrounding our 358-gene panel, the JAX Cancer Treatment Profile (JAX CTP), and supports annotation of functional significance of molecular variants. Through queries of data housed in JAX-CKB, we have analyzed the landscape of clinical trials relevant to our 358-gene targeted sequencing panel to evaluate strengths and weaknesses in current molecular targeting in oncology. Through this analysis, we have identified patient indications, molecular aberrations, and targeted therapy classes that have strong or weak representation in clinical trials. Conclusions Here, we describe the development and disseminate system methods for associating patient genomic sequence data with clinically relevant information, facilitating interpretation and providing a mechanism for informing therapeutic decision-making. Additionally, through customized queries, we have the capability to rapidly analyze the landscape of targeted therapies in clinical trials, enabling a unique view into current therapeutic availability in oncology.
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Affiliation(s)
- Sara E Patterson
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
| | - Rangjiao Liu
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
| | - Cara M Statz
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
| | - Daniel Durkin
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
| | | | - Susan M Mockus
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
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Emerging Biomarkers in Personalized Therapy of Lung Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 890:25-36. [DOI: 10.1007/978-3-319-24932-2_2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Daga A, Ansari A, Patel S, Mirza S, Rawal R, Umrania V. Current Drugs and Drug Targets in Non-Small Cell Lung Cancer: Limitations and Opportunities. Asian Pac J Cancer Prev 2015; 16:4147-56. [DOI: 10.7314/apjcp.2015.16.10.4147] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Choi YJ, Kim SY, So KS, Baek IJ, Kim WS, Choi SH, Lee JC, Bivona TG, Rho JK, Choi CM. AUY922 effectively overcomes MET- and AXL-mediated resistance to EGFR-TKI in lung cancer cells. PLoS One 2015; 10:e0119832. [PMID: 25780909 PMCID: PMC4363657 DOI: 10.1371/journal.pone.0119832] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 01/16/2015] [Indexed: 11/27/2022] Open
Abstract
The activation of bypass signals, such as MET and AXL, has been identified as a possible mechanism of EGFR-TKI resistance. Because various oncoproteins depend on HSP90 for maturation and stability, we investigated the effects of AUY922, a newly developed non-geldanamycin class HSP90 inhibitor, in lung cancer cells with MET- and AXL-mediated resistance. We established resistant cell lines with HCC827 cells harboring an exon 19-deletion mutation in of the EGFR gene via long-term exposure to increasing concentrations of gefitinib and erlotinib (HCC827/GR and HCC827/ER, respectively). HCC827/GR resistance was mediated by MET activation, whereas AXL activation caused resistance in HCC827/ER cells. AUY922 treatment effectively suppressed proliferation and induced cell death in both resistant cell lines. Accordingly, the downregulation of EGFR, MET, and AXL led to decreased Akt activation. The inhibitory effects of AUY922 on each receptor were confirmed in gene-transfected LK2 cells. AUY922 also effectively controlled tumor growth in xenograft mouse models containing HCC827/GR and HCC827/ER cells. In addition, AUY922 reduced invasion and migration by both types of resistant cells. Our study findings thus show that AUY922 is a promising therapeutic option for MET- and AXL-mediated resistance to EGFR-TKI in lung cancer.
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Affiliation(s)
- Yun Jung Choi
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
- Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Seon Ye Kim
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Kwang Sup So
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - In-Jeoung Baek
- Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Woo Sung Kim
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Se Hoon Choi
- Thoracic and Cardiovascular Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Jae Cheol Lee
- Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Trever G. Bivona
- Division of Hematology/Oncology, Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America
| | - Jin Kyung Rho
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
- Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
- * E-mail: (JKR); (CMC)
| | - Chang-Min Choi
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
- Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
- * E-mail: (JKR); (CMC)
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Wang X, Batty KM, Crowe PJ, Goldstein D, Yang JL. The Potential of panHER Inhibition in Cancer. Front Oncol 2015; 5:2. [PMID: 25674538 PMCID: PMC4309158 DOI: 10.3389/fonc.2015.00002] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 01/07/2015] [Indexed: 12/22/2022] Open
Abstract
Purpose: Hyper-activation of the HER (erbB) family receptors, HER 1-4, leads to up-regulation of the three vital signaling pathways: mitogen activated protein kinase, phosphoinositide 3-kinase/AKT, and Janus kinase/signal transducer and activator of transcription pathways. Blocking HER1/EGFR has a limited anticancer effect due to either secondary mutation e.g., T790M or by-pass signaling of other HER members. The emergence of an anti-panHER approach to blockade of these pathways as a cancer treatment may provide a solution to this resistance. This review aimed to provide an overview of the HER signaling pathways and their involvement in tumor progression and examine the current progress in panHER inhibition. Methods: Recent literature associated with HER signaling pathways and panHER inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis. Results: Pre-clinical studies and clinical trials of panHER inhibitors show promising results, and the potential to improve patient outcomes in solid cancers. Conclusion: The use of panHER inhibitors in cancers with HER-family hyper-activation, such as other epithelial cancers and sarcoma, is a new direction to research and has potential in clinical cancer therapy in the future.
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Affiliation(s)
- Xiaochun Wang
- Sarcoma Nano-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia ; Department of Surgery, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia
| | - Kathleen M Batty
- Sarcoma Nano-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia ; Department of Surgery, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia
| | - Philip J Crowe
- Sarcoma Nano-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia ; Department of Surgery, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia
| | - David Goldstein
- Sarcoma Nano-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia ; Department of Medical Oncology, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia
| | - Jia-Lin Yang
- Sarcoma Nano-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia ; Department of Surgery, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia
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Gollard R, Garcia D, Natale R. Pulmonary squamous cell carcinoma and sorafenib. Clin Case Rep 2015; 2:206-8. [PMID: 25614813 PMCID: PMC4302627 DOI: 10.1002/ccr3.95] [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: 01/10/2014] [Revised: 02/25/2014] [Accepted: 03/11/2014] [Indexed: 11/09/2022] Open
Abstract
KEY CLINICAL MESSAGE Pulmonary squamous cell carcinomas are not often thought to sensitive to targeted agents, like their cousin the adenocarcinoma of the lung. With appropriate testing of molecular markers, squamous cell carcinomas, like adenocarcinomas of the lung, melanomas, and renal cell carcinomas, may be found to be sensitive to newer, targeted agents.
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Affiliation(s)
- Russell Gollard
- Cancer & Blood Specialists of Nevada 2460 W. Horizon Ridge Pkwy., Henderson, Nevada, 89052
| | - Diana Garcia
- Quest Diagnostics 4230 Burnham Ave., Las Vegas, Nevada, 89119
| | - Ron Natale
- Cedars-Sinai Comprehensive Cancer Center 8700 Beverly Blvd, Suite AC10, West Hollywood, California, 90048
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Gara RK, Kumari S, Ganju A, Yallapu MM, Jaggi M, Chauhan SC. Slit/Robo pathway: a promising therapeutic target for cancer. Drug Discov Today 2015; 20:156-64. [PMID: 25245168 PMCID: PMC4445861 DOI: 10.1016/j.drudis.2014.09.008] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 08/19/2014] [Accepted: 09/12/2014] [Indexed: 12/19/2022]
Abstract
Axon guidance molecules, slit glycoprotein (Slit) and Roundabout receptor (Robo), have implications in the regulation of physiological processes. Recent studies indicate that Slit and Robo also have important roles in tumorigenesis, cancer progression and metastasis. The Slit/Robo pathway can be considered a master regulator for multiple oncogenic signaling pathways. Herein, we provide a comprehensive review on the role of these molecules and their associated signaling pathways in cancer progression and metastasis. Overall, the current available data suggest that the Slit/Robo pathway could be a promising target for development of anticancer drugs.
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Affiliation(s)
- Rishi K Gara
- Department of Pharmaceutical Sciences and Center for Cancer Research, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Sonam Kumari
- Department of Pharmaceutical Sciences and Center for Cancer Research, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Aditya Ganju
- Department of Pharmaceutical Sciences and Center for Cancer Research, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Murali M Yallapu
- Department of Pharmaceutical Sciences and Center for Cancer Research, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Meena Jaggi
- Department of Pharmaceutical Sciences and Center for Cancer Research, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Subhash C Chauhan
- Department of Pharmaceutical Sciences and Center for Cancer Research, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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Schildhaus HU, Schultheis AM, Rüschoff J, Binot E, Merkelbach-Bruse S, Fassunke J, Schulte W, Ko YD, Schlesinger A, Bos M, Gardizi M, Engel-Riedel W, Brockmann M, Serke M, Gerigk U, Hekmat K, Frank KF, Reiser M, Schulz H, Krüger S, Stoelben E, Zander T, Wolf J, Buettner R. MET amplification status in therapy-naïve adeno- and squamous cell carcinomas of the lung. Clin Cancer Res 2014; 21:907-15. [PMID: 25492085 DOI: 10.1158/1078-0432.ccr-14-0450] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer. EXPERIMENTAL DESIGN We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC. RESULTS Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations. CONCLUSION MET amplification is not a mutually exclusive genetic event in therapy-naïve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors.
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Affiliation(s)
- Hans-Ulrich Schildhaus
- Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Institute of Pathology, University Hospital Göttingen, Göttingen, Germany.
| | - Anne M Schultheis
- Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany
| | - Josef Rüschoff
- Institute of Pathology Nordhessen, Kassel, Germany. Targos Molecular Pathology, Kassel, Germany
| | - Elke Binot
- Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany
| | - Sabine Merkelbach-Bruse
- Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany
| | - Jana Fassunke
- Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany
| | - Wolfgang Schulte
- Thoraxzentrum im Malteser Krankenhaus Bonn/Rhein-Sieg, Bonn, Germany
| | - Yon-Dschun Ko
- Johanniter-Krankenhaus, Evangelische Kliniken Bonn GmbH, Bonn, Germany
| | | | - Marc Bos
- Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Department I of Internal Medicine and Centre of Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany
| | - Masyar Gardizi
- Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Department I of Internal Medicine and Centre of Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany
| | | | - Michael Brockmann
- Institute of Pathology, Kliniken der Stadt Köln GmbH, Cologne, Germany
| | | | - Ulrich Gerigk
- Thoraxzentrum im Malteser Krankenhaus Bonn/Rhein-Sieg, Bonn, Germany
| | - Khosro Hekmat
- Department of Cardiothoracic Surgery, University of Cologne, Cologne, Germany
| | - Konrad F Frank
- Department III of Internal Medicine, University of Cologne, Cologne, Germany
| | - Marcel Reiser
- PIOH-Praxis Internistischer Onkologie und Hämatologie Köln, Cologne, Germany
| | - Holger Schulz
- PIOH-Praxis Internistischer Onkologie und Hämatologie Frechen, Frechen, Germany
| | - Stefan Krüger
- Florence Nightingale Krankenhaus Düsseldorf Kaiserswerth, Düsseldorf, Germany
| | - Erich Stoelben
- Lungenklinik Merheim, Kliniken der Stadt Köln GmbH, Cologne, Germany
| | - Thomas Zander
- Department I of Internal Medicine and Centre of Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany. NGM, Network Genomic Medicine and GCGC, Gastrointestinal Cancer Group Cologne, Germany
| | - Jürgen Wolf
- Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Department I of Internal Medicine and Centre of Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany
| | - Reinhard Buettner
- Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Targos Molecular Pathology, Kassel, Germany
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Li ZX, Qu LY, Wen H, Zhong HS, Xu K, Qiu XS, Wang EH. Mig-6 overcomes gefitinib resistance by inhibiting EGFR/ERK pathway in non-small cell lung cancer cell lines. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:7304-7311. [PMID: 25400829 PMCID: PMC4230080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 08/20/2014] [Indexed: 06/04/2023]
Abstract
Non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and is the most common cause of lung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is widely used for patients with advanced NSCLC. However, drug resistance is a major obstacle. Mig-6 is a feedback inhibitor of EGFR and its down-stream pathway; it has been shown to play a role in gefitinib sensitivity. There is neither systematical research on the relationship between Mig-6 expression and gefitinib sensitivity, nor has the contribution of up-regulated Mig-6 on the gefitinib-resistant cell lines. In the present work, four NSCLC cell lines (H1299, A549, PC-9, and PC-9/AB11) with different sensitivities to gefitinib were subjected to analysis of the expression of Mig-6. We found that Mig-6 is over-expressed in gefitinib-sensitive NSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Further analysis revealed that over-expression of Mig-6 increased cell apoptosis and inhibited proliferation of gefitinib-resistant NSCLC cells treated with gefitinib, whereas lowering the expression of Mig-6 decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in gefitinib-sensitive NSCLC cell lines. These results suggest that Mig-6 is involved in mediating the response to gefitinib in NSCLC cell lines. Additionally we demonstrated that Mig-6 could reverse gefitinib resistance through inhibition of EGFR/ERK pathway in NSCLC cells. Our work uncovered that Mig-6 may be an effective therapeutic target in gefitinib-resistant lung cancer patients.
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Affiliation(s)
- Zi-Xuan Li
- Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology, The First Affiliated Hospital of China Medical UniversityShenyang 110001, P. R. China
- Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical UniversityShenyang 110001, P. R. China
| | - Lian-Yue Qu
- Department of Pharmacy, The First Affiliated Hospital of China Medical UniversityShenyang 110001, P. R. China
| | - Hi Wen
- Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical UniversityShenyang 110001, P. R. China
- Shiyan Taihe HospitalShiyan 442000, P. R. China
| | - Hong-Shan Zhong
- Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology, The First Affiliated Hospital of China Medical UniversityShenyang 110001, P. R. China
| | - Ke Xu
- Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology, The First Affiliated Hospital of China Medical UniversityShenyang 110001, P. R. China
| | - Xue-Shan Qiu
- Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical UniversityShenyang 110001, P. R. China
| | - En-Hua Wang
- Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical UniversityShenyang 110001, P. R. China
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Fisher KE, Pillai RN, Kudchadkar RR, Rossi MR. Section IV: non-small cell lung cancer and malignant melanoma. Curr Probl Cancer 2014; 38:180-98. [PMID: 25281457 DOI: 10.1016/j.currproblcancer.2014.08.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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Korpanty GJ, Graham DM, Vincent MD, Leighl NB. Biomarkers That Currently Affect Clinical Practice in Lung Cancer: EGFR, ALK, MET, ROS-1, and KRAS. Front Oncol 2014; 4:204. [PMID: 25157335 PMCID: PMC4127527 DOI: 10.3389/fonc.2014.00204] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 07/16/2014] [Indexed: 12/31/2022] Open
Abstract
Lung cancer remains the most lethal malignancy in the world. Despite improvements in surgical treatment, systemic therapy, and radiotherapy, the 5-year survival rate for all patients diagnosed with lung cancer remains between 15 and 20%. Newer therapeutic strategies rely on specific molecular alterations, or biomarkers, that provide opportunities for a personalized approach to specific patient populations. Classification of lung cancer is becoming increasingly focused on these biomarkers, which renders the term "non-small cell lung" cancer less clinically useful. Non-small cell lung cancer is now recognized as a complex malignancy and its molecular and genomic diversity allows for patient-centered treatment options. Here, we review advances in targeted treatment of lung adenocarcinoma with respect to five clinically relevant biomarkers - EGFR, ALK, MET, ROS-1, and KRAS.
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Affiliation(s)
- Grzegorz J. Korpanty
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Donna M. Graham
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Mark D. Vincent
- London Regional Cancer Program, Department of Medical Oncology, London Health Sciences Centre, London, ON, Canada
| | - Natasha B. Leighl
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
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Spampatti M, Vlotides G, Spöttl G, Maurer J, Göke B, Auernhammer CJ. Aspirin inhibits cell viability and mTOR downstream signaling in gastroenteropancreatic and bronchopulmonary neuroendocrine tumor cells. World J Gastroenterol 2014; 20:10038-10049. [PMID: 25110431 PMCID: PMC4123333 DOI: 10.3748/wjg.v20.i29.10038] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of aspirin on neuroendocrine tumor (NET) cell growth and signaling in vitro.
METHODS: Human pancreatic BON1, bronchopulmonary NCI-H727 and midgut GOT1 neuroendocrine tumor cells were treated with different concentrations of aspirin (from 0.001 to 5 mmol/L), and the resulting effects on metabolic activity/cell proliferation were measured using cell proliferation assays and SYBR-DNA-labeling after 72, 144 and 216 h of incubation. The effects of aspirin on the expression and phosphorylation of several critical proteins that are involved in the most common intracellular growth factor signaling pathways (especially Akt protein kinase B) and mammalian target of rapamycin (mTOR) were determined by Western blot analyses. Propidium iodide staining and flow cytometry were used to evaluate changes in cell cycle distribution and apoptosis. Statistical analysis was performed using a 2-tailed Student’s t-test to evaluate the proliferation assays and cell cycle analyses. The results are expressed as the mean ± SD of 3 or 4 independently performed experiments. Statistical significance was set at P < 0.05.
RESULTS: Treatment with aspirin suppressed the viability/proliferation of BON1, NCI-H727 and GOT1 cells in a time- and dose-dependent manner. Significant effects were observed at starting doses of 0.5-1 mmol/L and peaked at 5 mmol/L. For instance, after treatment with 1 mmol/L aspirin for 144 h, the viability of pancreatic BON1 cells decreased to 66% ± 13% (P < 0.05), the viability of bronchopulmonary NCI-H727 cells decreased to 53% ± 8% (P < 0.01) and the viability of midgut GOT1 cells decreased to 89% ± 6% (P < 0.01). These effects were associated with a decreased entry into the S phase, the induction of the cyclin-dependent kinase inhibitor p21 and reduced expression of cyclin-dependent kinase 4 and cyclin D3. Aspirin suppressed mTOR downstream signaling, evidenced by the reduced phosphorylation of the mTOR substrates 4E binding protein 1, serine/threonine kinase P70S6K and S6 ribosomal protein and inhibited glycogen synthase kinase 3 activity. We observed the (compensatory) activation of tuberous sclerosis 2, the serine/threonine specific protein kinase AKT and extracellular signal-regulated kinases.
CONCLUSION: Aspirin demonstrates promising anticancer properties for NETs in vitro. Further preclinical and clinical studies are needed.
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