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Miglietta G, Russo M, Capranico G, Marinello J. Stimulation of cGAS-STING pathway as a challenge in the treatment of small cell lung cancer: a feasible strategy? Br J Cancer 2024; 131:1567-1575. [PMID: 39215193 PMCID: PMC11555062 DOI: 10.1038/s41416-024-02821-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/03/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024] Open
Abstract
Lung cancer has a significant incidence among the population and, unfortunately, has an unfavourable prognosis in most cases. The World Health Organization (WHO) classifies lung tumours into two subtypes based on their phenotype: the Non-Small Cell Lung Cancer (NSCLC) and the Small Cell Lung Cancer (SCLC). SCLC treatment, despite advances in chemotherapy and radiotherapy, is often unsuccessful for cancer recurrence highlighting the need to develop novel therapeutic strategies. In this review, we describe the genetic landscape and tumour microenvironment that characterize the pathological processes of SCLC and how they are responsible for tumour immune evasion. The immunosuppressive mechanisms engaged in SCLC are critical factors to understand the failure of immunotherapy in SCLC and, conversely, suggest that new signalling pathways, such as cGAS/STING, should be investigated as possible targets to stimulate an innate immune response in this subtype of lung cancer. The full comprehension of the innate immunity of cancer cells is thus crucial to open new challenges for successful immunotherapy in treating SCLC and improving patient outcomes.
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Affiliation(s)
- Giulia Miglietta
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Marco Russo
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Giovanni Capranico
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
| | - Jessica Marinello
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
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Trillo Aliaga P, Del Signore E, Fuorivia V, Spitaleri G, Asnaghi R, Attili I, Corvaja C, Carnevale Schianca A, Passaro A, de Marinis F. The Evolving Scenario of ES-SCLC Management: From Biology to New Cancer Therapeutics. Genes (Basel) 2024; 15:701. [PMID: 38927637 PMCID: PMC11203015 DOI: 10.3390/genes15060701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/13/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.
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Affiliation(s)
- Pamela Trillo Aliaga
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Ester Del Signore
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Valeria Fuorivia
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Gianluca Spitaleri
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Riccardo Asnaghi
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Ilaria Attili
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Carla Corvaja
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Ambra Carnevale Schianca
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Antonio Passaro
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Filippo de Marinis
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
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Luciani A, Blasi M, Provenzano L, Zonato S, Ferrari D. Recent advances in small cell lung cancer: the future is now? Minerva Endocrinol (Torino) 2022; 47:460-474. [PMID: 33331739 DOI: 10.23736/s2724-6507.20.03213-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Small cell lung cancer is a relevant clinical issue as it is a highly malignant cancer, often diagnosed in advanced stage. Similarly to non-small cell lung cancer, tobacco smoking is currently the main risk factor. Its incidence, at least in males, has declined over the past decades, due to the worldwide decreased percentage of active smokers. The typical small cells of this tumor type are characterized by a high Proliferation Index, chromosomal deletions such as 3p(14-23) involving the tumor-suppressor gene FHIT, alterations of the MYC or Notch family proteins and the frequent expression of neuroendocrine markers. The combination of thoracic radiotherapy and chemotherapy is the standard treatment for limited stage disease, while platinum-based chemotherapy is the most effective choice for extensive stage disease. Unfortunately, whatever chemotherapy is used, the results are disappointing. No regimen has proved to be effective in the long run, indeed small cell lung cancer rapidly progresses after a frequent initial strong response, and the mortality rate remains still high. The advent of immunotherapy is actually changing the landscape in oncology. As well as in other cancers, recent trials have demonstrated the efficacy of the combination of immune checkpoint inhibitors and chemotherapy, opening new perspectives for the future of our patients.
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Affiliation(s)
- Andrea Luciani
- Unit of Medical Oncology, San Paolo Hospital, Milan, Italy -
| | - Miriam Blasi
- Unit of Medical Oncology, San Paolo Hospital, Milan, Italy
| | | | - Sabrina Zonato
- Unit of Medical Oncology, San Paolo Hospital, Milan, Italy
| | - Daris Ferrari
- Unit of Medical Oncology, San Paolo Hospital, Milan, Italy
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Hung MC, Wang WP, Chi YH. AKT phosphorylation as a predictive biomarker for PI3K/mTOR dual inhibition-induced proteolytic cleavage of mTOR companion proteins in small cell lung cancer. Cell Biosci 2022; 12:122. [PMID: 35918763 PMCID: PMC9344631 DOI: 10.1186/s13578-022-00862-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/22/2022] [Indexed: 11/21/2022] Open
Abstract
Background Constitutive activation of PI3K signaling has been well recognized in a subset of small cell lung cancer (SCLC), the cancer type which has the most aggressive clinical course amongst pulmonary tumors. Whereas cancers that acquire a mutation/copy gain in PIK3CA or loss of PTEN have been implicated in enhanced sensitivity to inhibitors targeting the PI3K/AKT/mTOR pathway, the complexities of the pathway and corresponding feedback loops hamper clear predictions as to the response of tumors presenting these genomic features. Methods The correlation between the expression profile of proteins involved in the PI3K/AKT/mTOR signaling and cell viability in response to treatment with small molecule inhibitors targeting isoform-specific PI3Ks, AKT, and mTOR was assessed in 13 SCLC cancer cell lines. Athymic nude mice were used to determine the effect of PI3K/mTOR dual inhibition on the growth of xenograft SCLC tumors in vivo. The activation of caspase signaling and proteolytic cleavages of mTOR companion proteins were assessed using recombinant caspases assays and Western blot analyses. Results Our results indicate that the sensitivity of these SCLC cell lines to GSK2126458, a dual PI3K/mTOR inhibitor, is positively correlated with the expression levels of phosphorylated AKT (p-AKT) at Thr308 and Ser473. Inhibition of pan-class I PI3Ks or PI3K/mTOR dual inhibition was shown to induce proteolytic cleavage of RICTOR and RPTOR, which were respectively dependent on Caspase-6 and Caspase-3. A combination of a clinically approved PI3Kα-selective inhibitor and an mTORC1 inhibitor was shown to have synergistic effects in inducing the death of SCLC cells with high p-AKT. We observed no clear correlation between PTEN levels and the survival of SCLCs in response to PI3K/mTOR dual inhibition; however, PTEN depletion was shown to increase the susceptibility of low p-AKT SCLC cells to dual PI3K/mTOR inhibitor-induced cell death as well as the proteolytic cleavage of RICTOR. Conclusions These results suggest the level of p-AKT can be a companion diagnostic biomarker for the treatment of SCLC involving the combinational use of clinically approved isoform-specific PI3K and mTOR inhibitors. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00862-y.
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Wang WZ, Shulman A, Amann JM, Carbone DP, Tsichlis PN. Small cell lung cancer: Subtypes and therapeutic implications. Semin Cancer Biol 2022; 86:543-554. [DOI: 10.1016/j.semcancer.2022.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/23/2022] [Accepted: 04/04/2022] [Indexed: 12/20/2022]
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Mirzaei G, Petreaca RC. Distribution of copy number variations and rearrangement endpoints in human cancers with a review of literature. Mutat Res 2022; 824:111773. [PMID: 35091282 PMCID: PMC11301607 DOI: 10.1016/j.mrfmmm.2021.111773] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/08/2021] [Accepted: 12/10/2021] [Indexed: 12/13/2022]
Abstract
Copy number variations (CNVs) which include deletions, duplications, inversions, translocations, and other forms of chromosomal re-arrangements are common to human cancers. In this report we investigated the pattern of these variations with the goal of understanding whether there exist specific cancer signatures. We used re-arrangement endpoint data deposited on the Catalogue of Somatic Mutations in Cancers (COSMIC) for our analysis. Indeed, we find that human cancers are characterized by specific patterns of chromosome rearrangements endpoints which in turn result in cancer specific CNVs. A review of the literature reveals tissue specific mutations which either drive these CNVs or appear as a consequence of CNVs because they confer an advantage to the cancer cell. We also identify several rearrangement endpoints hotspots that were not previously reported. Our analysis suggests that in addition to local chromosomal architecture, CNVs are driven by the internal cellular or nuclear physiology of each cancer tissue.
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Affiliation(s)
- Golrokh Mirzaei
- Department of Computer Science and Engineering, The Ohio State University at Marion, Marion, OH, 43302, USA
| | - Ruben C Petreaca
- Department of Molecular Genetics, The Ohio State University at Marion, Marion, OH, 43302, USA; Cancer Biology Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, 43210, USA.
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Wang Y, Qian F, Chen Y, Yang Z, Hu M, Lu J, Zhang Y, Zhang W, Cheng L, Han B. Comparative Study of Pulmonary Combined Large-Cell Neuroendocrine Carcinoma and Combined Small-Cell Carcinoma in Surgically Resected High-Grade Neuroendocrine Tumors of the Lung. Front Oncol 2021; 11:714549. [PMID: 34631540 PMCID: PMC8493068 DOI: 10.3389/fonc.2021.714549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 09/03/2021] [Indexed: 12/25/2022] Open
Abstract
Objectives Pulmonary large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are both classified as pure and combined subtypes. Due to the low incidence and difficult diagnosis of combined LCNEC (C-LCNEC) and combined SCLC (C-SCLC), few studies have compared their clinical features and prognosis. Materials and Methods We compared the clinical features, mutation status of driver genes (EGFR, ALK, ROS1, KRAS, and BRAF), and prognosis between C-LCNEC and C-SCLC. Univariate and multivariate Cox regression analyses were applied for survival analysis. Results We included a total of 116 patients with C-LCNEC and 76 patients with C-SCLC in the present study. There were significant differences in distribution of smoking history, tumor location, pT stage, pN stage, pTNM stage, visceral pleural invasion (VPI), and combined components between C-LCNEC and C-SCLC (P<0.05 for all). C-SCLC was more advanced at diagnosis as compared to C-LCNEC. The incidence of EGFR mutations in C-LCNEC patients was higher than C-SCLC patients (25.7 vs. 5%, P=0.004). We found that tumor size, pN stage, peripheral CEA level, and adjuvant chemotherapy were independently prognostic factors for DFS and OS in C-LCNEC patients, while peripheral NSE level, pT stage, pN stage, VPI and adjuvant chemotherapy were independently associated with DFS and OS for C-SCLC patients (P<0.05 for all). Propensity score matching with adjustment for the confounders confirmed a more favorable DFS (P=0.032) and OS (P=0.019) in patients with C-LCNEC in comparison with C-SCLC patients upon survival analysis. Conclusions The mutation landscape of driver genes seemed to act in different way between C-SCLC and C-LCNEC, likely by which result in clinical phenotype difference as well as better outcome in C-LCNEC.
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Affiliation(s)
- Yanan Wang
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Fangfei Qian
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ya Chen
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhengyu Yang
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Minjuan Hu
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Lu
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yanwei Zhang
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Zhang
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Cheng
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Baohui Han
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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Thankamony AP, Subbalakshmi AR, Jolly MK, Nair R. Lineage Plasticity in Cancer: The Tale of a Skin-Walker. Cancers (Basel) 2021; 13:3602. [PMID: 34298815 PMCID: PMC8306016 DOI: 10.3390/cancers13143602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/04/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022] Open
Abstract
Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here, we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of epithelial-mesenchymal transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.
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Affiliation(s)
- Archana P. Thankamony
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India;
- Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Ayalur Raghu Subbalakshmi
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Radhika Nair
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India;
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Pandey M, Mukhopadhyay A, Sharawat SK, Kumar S. Role of microRNAs in regulating cell proliferation, metastasis and chemoresistance and their applications as cancer biomarkers in small cell lung cancer. Biochim Biophys Acta Rev Cancer 2021; 1876:188552. [PMID: 33892053 DOI: 10.1016/j.bbcan.2021.188552] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 12/22/2022]
Abstract
Small cell lung cancer (SCLC), a smoking-related highly aggressive neuroendocrine cancer, is characterized by rapid cell proliferation, early metastatic dissemination, and early relapse due to chemoresistance to first-line platinum-doublet chemotherapy. Genomically, SCLC tumors show nearly universal loss of TP53 and RB1 tumor suppressor genes, while gene expression signature classifies them into 4 distinct subgroups based on the expression patterns of lineage transcription factors - ASCL1/ASH1, NEUROD1, YAP-1, and POU2F3. Due to the lack of targetable molecular alterations and clinically useful diagnostic, prognostic and predictive biomarker, there is insignificant progress in the therapeutic management of SCLC patients. Numerous studies have shown a significant involvement of non-coding RNAs in the regulation of cell proliferation, invasion and migration, apoptosis, metastasis, and chemoresistance in various human cancers. In this review, we comprehensively discuss the role of microRNAs (miRNAs) in regulating the aforementioned biological process in SCLC. For this, we searched the scientific literature and selected studies that have evaluated the role of miRNAs in the disease pathogenesis or as a cancer biomarker in SCLC. Our review suggests that several miRNAs are involved in the pathogenesis of SCLC mainly by regulating cell proliferation, metastasis, and chemoresistance. Few studies have also demonstrated the clinical utility of miRNAs in monitoring response to chemotherapy as well as in predicting survival outcomes. However, more in-depth mechanistic studies utilizing in vivo models and multicentric studies with larger patient cohorts are needed before the applications of miRNAs as therapeutic targets or as biomarkers are translated from the laboratory into clinics.
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Affiliation(s)
- Monu Pandey
- Dept. of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
| | - Abhirup Mukhopadhyay
- Dept. of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
| | - Surender K Sharawat
- Dept. of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
| | - Sachin Kumar
- Dept. of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
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Andonegui-Elguera SD, Zamora-Fuentes JM, Espinal-Enríquez J, Hernández-Lemus E. Loss of Long Distance Co-Expression in Lung Cancer. Front Genet 2021; 12:625741. [PMID: 33777098 PMCID: PMC7987938 DOI: 10.3389/fgene.2021.625741] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/29/2021] [Indexed: 12/13/2022] Open
Abstract
Lung cancer is one of the deadliest, most aggressive cancers. Abrupt changes in gene expression represent an important challenge to understand and fight the disease. Gene co-expression networks (GCNs) have been widely used to study the genomic regulatory landscape of human cancer. Here, based on 1,143 RNA-Seq experiments from the TCGA collaboration, we constructed GCN for the most common types of lung tumors: adenocarcinoma (TAD) and squamous cells (TSCs) as well as their respective control networks (NAD and NSC). We compared the number of intra-chromosome (cis-) and inter-chromosome (trans-) co-expression interactions in normal and cancer GCNs. We compared the number of shared interactions between TAD and TSC, as well as in NAD and NSC, to observe which phenotypes were more alike. By means of an over-representation analysis, we associated network topology features with biological functions. We found that TAD and TSC present mostly cis- small disconnected components, whereas in control GCNs, both types have a giant trans- component. In both cancer networks, we observed cis- components in which genes not only belong to the same chromosome but to the same cytoband or to neighboring cytobands. This supports the hypothesis that in lung cancer, gene co-expression is constrained to small neighboring regions. Despite this loss of distant co-expression observed in TAD and TSC, there are some remaining trans- clusters. These clusters seem to play relevant roles in the carcinogenic processes. For instance, some clusters in TAD and TSC are associated with the immune system, response to virus, or control of gene expression. Additionally, other non-enriched trans- clusters are composed of one gene and several associated pseudo-genes, as in the case of the FTH1 gene. The appearance of those common trans- clusters reflects that the gene co-expression program in lung cancer conserves some aspects for cell maintenance. Unexpectedly, 0.48% of the edges are shared between control networks; conversely, 35% is shared between lung cancer GCNs, a 73-fold larger intersection. This suggests that in lung cancer a process of de-differentiation may be occurring. To further investigate the implications of the loss of distant co-expression, it will become necessary to broaden the investigation with other omic-based approaches. However, the present approach provides a basis for future work toward an integrative perspective of abnormal transcriptional regulatory programs in lung cancer.
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Affiliation(s)
| | | | - Jesús Espinal-Enríquez
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.,Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Enrique Hernández-Lemus
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.,Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Zhang B, Birer SR, Dvorkin M, Shruti J, Byers L. New Therapies and Biomarkers: Are We Ready for Personalized Treatment in Small Cell Lung Cancer? Am Soc Clin Oncol Educ Book 2021; 41:1-10. [PMID: 33979194 DOI: 10.1200/edbk_320673] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a 5-year survival rate of less than 7%. In contrast to non-small cell lung cancer, SCLC has long been treated as a homogeneous disease without personalized treatment options. In recent years, the incorporation of immunotherapy into the treatment paradigm has brought moderate benefit to patients with SCLC; however, more effective therapies are urgently needed. In this article, we describe the current treatment standards and emerging therapeutic approaches for the treatment of SCLC. We also discuss promising biomarkers in SCLC and the recently discovered four subtypes of SCLC, each with its unique therapeutic vulnerability. Lastly, we discuss the advances in radiation therapy for the treatment of SCLC.
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Affiliation(s)
- Bingnan Zhang
- Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX
| | - Samuel R Birer
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI
| | - Mikhail Dvorkin
- BHI of Omsk Region Clinical Oncology Dispensary, Omsk, Russia
| | - Jolly Shruti
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI
| | - Lauren Byers
- Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX
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12
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History of Extensive Disease Small Cell Lung Cancer Treatment: Time to Raise the Bar? A Review of the Literature. Cancers (Basel) 2021; 13:cancers13050998. [PMID: 33673630 PMCID: PMC7957518 DOI: 10.3390/cancers13050998] [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: 01/26/2021] [Revised: 02/11/2021] [Accepted: 02/19/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Small cell lung cancer (SCLC) remains the most aggressive form of neuroendocrine tumor of the lung, for which treatment options remain limited. The introduction of immune checkpoint inhibitors has modified for the first time the therapeutic strategies in patients with extensive disease after decades. New therapeutic approaches are required. Deeper knowledge of tumor biology is required to gain new insights into this complex disease. Abstract Several trials have tried for decades to improve the outcome of extensive disease small cell lung cancer (ED-SCLC) through attempts to modify the standard treatments. Nevertheless, platinum/etoposide combination and topotecan have remained respectively the first and the second line standard treatments for the last 40 years. With the advent of immunotherapy, this scenario has finally changed. Our review aims to provide an overview of the primary studies on the actual therapeutic strategies available for ED-SCLC patients, and to highlight emerging evidence supporting the use of immunotherapy in SCLC patients.
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13
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Kumar S, Pandey M, Sharawat SK. Biological functions of long noncoding RNAs and circular RNAs in small-cell lung cancer. Epigenomics 2020; 12:1751-1763. [DOI: 10.2217/epi-2020-0214] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
We aim to discuss comprehensively the role of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in small-cell lung cancer (SCLC) biology and their clinical utility as cancer biomarkers. We searched the scientific literature to select articles related to the role of lncRNAs and circRNAs in SCLC biology or as cancer biomarkers. We identified that a number of lncRNAs and circRNAs can regulate key biological processes involved in SCLC development, including cell proliferation, metastasis and chemoresistance mainly acting as miRNA sponges. Also, the expression of a few lncRNAs and circRNAs predicted survival outcome depicting their utility as prognostic biomarkers. Further investigations on the role of lncRNAs and circRNAs in SCLC tumors may yield novel therapeutic targets for SCLC.
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Affiliation(s)
- Sachin Kumar
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
| | - Monu Pandey
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
| | - Surender K Sharawat
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
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14
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Yeung YT, Fan S, Lu B, Yin S, Yang S, Nie W, Wang M, Zhou L, Li T, Li X, Bode AM, Dong Z. CELF2 suppresses non-small cell lung carcinoma growth by inhibiting the PREX2-PTEN interaction. Carcinogenesis 2020; 41:377-389. [PMID: 31241130 DOI: 10.1093/carcin/bgz113] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 06/03/2019] [Accepted: 06/20/2019] [Indexed: 12/31/2022] Open
Abstract
The phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway is important in the regulation of cell proliferation through its production of phosphatidylinositol 3,4,5-triphosphate (PIP3). Activation of this pathway is frequently observed in human cancers, including non-small cell lung carcinoma. The PI3-K/Akt pathway is negatively regulated by the dual-specificity phosphatase and tensin homolog (PTEN) protein. PTEN acts as a direct antagonist of PI3-K by dephosphorylating PIP3. Studies have shown that PTEN phosphatase activity is inhibited by PREX2, a guanine nucleotide exchanger factor (GEF). Multiple studies revealed that CELF2, an RNA binding protein, cooperates synergistically with PTEN as a tumor suppressor in multiple cancers. However, the underlying mechanism as to how CELF2 enhances PTEN activity remains unclear. Here, we report that CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN. Consistent with this observation, PTEN phosphatase activity is upregulated with CELF2 overexpression. In addition, overexpression of CELF2 represses both Akt phosphorylation and cell proliferation only in the presence of PTEN. In an ex vivo study, CELF2 gene delivery could significantly inhibit patient-derived xenografts (PDX) tumor growth. To further investigate the clinical relevance of this finding, we analyzed 87 paired clinical lung adenocarcinoma samples and the results showed that CELF2 protein expression is downregulated in tumor tissues and associated with poor prognosis. The CELF2 gene is located on the chromosome 10p arm, a region frequently lost in human cancers, including breast invasive carcinoma, low-grade glioma and glioblastoma. Analysis of TCGA datasets showed that CELF2 expression is also associated with shorter patient survival time in all these cancers. Overall, our work suggests that CELF2 plays a novel role in PI3-K signaling by antagonizing the oncogenic effect of PREX2.
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Affiliation(s)
- Yiu To Yeung
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.,The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Suyu Fan
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Bingbing Lu
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.,Pathophysiology Department, Basic Medical College, Zhengzhou University, Zhengzhou, Henan, China
| | - Shuying Yin
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.,Pathophysiology Department, Basic Medical College, Zhengzhou University, Zhengzhou, Henan, China
| | - Sen Yang
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Wenna Nie
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Meixian Wang
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Liting Zhou
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Tiepeng Li
- Department of Immunotherapy, The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiang Li
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.,Pathophysiology Department, Basic Medical College, Zhengzhou University, Zhengzhou, Henan, China.,Collaborative Innovation Center of Cancer Chemoprevention of Henan, Zhengzhou, Henan, China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Zigang Dong
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.,The Hormel Institute, University of Minnesota, Austin, MN, USA.,Pathophysiology Department, Basic Medical College, Zhengzhou University, Zhengzhou, Henan, China.,Department of Immunotherapy, The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China.,Collaborative Innovation Center of Cancer Chemoprevention of Henan, Zhengzhou, Henan, China
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15
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Taniguchi H, Sen T, Rudin CM. Targeted Therapies and Biomarkers in Small Cell Lung Cancer. Front Oncol 2020; 10:741. [PMID: 32509576 PMCID: PMC7251180 DOI: 10.3389/fonc.2020.00741] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/20/2020] [Indexed: 12/13/2022] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid growth, early metastasis, and acquired therapeutic resistance. A majority of patients with SCLC have extensive-stage (ES) disease, defined as the presence of metastatic disease outside the hemithorax at first diagnosis. SCLC has been considered “a graveyard for drug development,” with chemotherapy remaining the standard treatment for first- and second-line management until quite recently. In contrast to NSCLC, identifying therapeutic targets in SCLC has been challenging, partly because driver mutations are primarily loss of function, involving the tumor suppressor genes RB1 and TP53 or currently untargetable (e.g., amplification of MYC family members). Recent gene expression profiling of SCLC cells lines, patient samples and representative murine models, have led to a proposed delineation of four major subtypes for SCLC distinguished by differential expression of four key transcriptional regulators (ASCL1, NEUROD1, POU2F3, and YAP1). Our understanding of the biology of SCLC has indeed significantly improved recently due to the continued efforts of the dedicated investigators in this field, but the therapeutic options remain dismal. While recent results from immunotherapy trials are encouraging, most patients demonstrate either primary or rapid acquired resistance to current regimens, highlighting the clear need to improve the effectiveness and expand the scope of current therapeutic strategies. In this opinion article, we will discuss recent developments in the treatment of SCLC, focused on current understanding of the signaling pathways, the role of immunotherapy and targeted therapy, and emerging biomarkers of response to therapy in SCLC.
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Affiliation(s)
- Hirokazu Taniguchi
- Molecular Pharmacology Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Triparna Sen
- Molecular Pharmacology Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Charles M Rudin
- Molecular Pharmacology Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
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16
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Shaurova T, Zhang L, Goodrich DW, Hershberger PA. Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer. Front Genet 2020; 11:281. [PMID: 32292420 PMCID: PMC7121227 DOI: 10.3389/fgene.2020.00281] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 03/09/2020] [Indexed: 12/19/2022] Open
Abstract
Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called “bypass activation”). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.
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Affiliation(s)
- Tatiana Shaurova
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Letian Zhang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - David W Goodrich
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Pamela A Hershberger
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
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17
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An outlined review for the role of Nedd4-1 and Nedd4-2 in lung disorders. Biomed Pharmacother 2020; 125:109983. [PMID: 32092816 DOI: 10.1016/j.biopha.2020.109983] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 01/30/2020] [Accepted: 01/31/2020] [Indexed: 12/16/2022] Open
Abstract
Neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase (Nedd4-1 and Nedd4-2) is a member of the HECT E3 ubiquitin ligase family. It has been shown to mediate numerous pathophysiological processes, including the regulation of synaptic plasticity and Wnt-associated signaling, via promoting the ubiquitination of its substrates, such as cyclic adenosine monophosphate (cAMP)-response element binding protein regulated transcription coactivator 3 (CRTC3), alpha-amino-3-hydroxy-5-methyl-4-isoxazo-lepropionic acid receptor (AMPAR), and Dishevelled2 (Dvl2). In the respiratory system, both Nedd4-1 and Nedd4-2 are expressed in epithelial cells and functionally associated with lung cancer development and alveolar fluid regulation. Nedd4-1 mediates lung cancer migration, metastasis, or drug resistance mainly through inducing phosphate and tension homology deleted on chromsome ten (PTEN) degradation or promoting cathepsin B secretion. Unlike Nedd4-1, Nedd4-2 displays more complex effects in lung cancers. On one hand it suppresses lung cancer cell migration and metastasis, and on the other hand it has been shown to promote lung cancer survival via inducing general control nonrepressed 2 (GCN2) degradation. Another important function of Nedd4-2 is to regulate the activity of epithelial sodium channel (ENaC), a membrane channel which mediates the clearance of fluid from the alveolar space at birth or during pulmonary edema. Here, we make an outlined review for the expression and function of Nedd4-1 and Nedd4-2 in the respiratory system in hope of getting an in-depth insight into their roles in lung disorders.
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18
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Wan Mohd Tajuddin WNB, Lajis NH, Abas F, Othman I, Naidu R. Mechanistic Understanding of Curcumin's Therapeutic Effects in Lung Cancer. Nutrients 2019; 11:E2989. [PMID: 31817718 PMCID: PMC6950067 DOI: 10.3390/nu11122989] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/22/2019] [Accepted: 11/30/2019] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is among the most common cancers with a high mortality rate worldwide. Despite the significant advances in diagnostic and therapeutic approaches, lung cancer prognoses and survival rates remain poor due to late diagnosis, drug resistance, and adverse effects. Therefore, new intervention therapies, such as the use of natural compounds with decreased toxicities, have been considered in lung cancer therapy. Curcumin, a natural occurring polyphenol derived from turmeric (Curcuma longa) has been studied extensively in recent years for its therapeutic effects. It has been shown that curcumin demonstrates anti-cancer effects in lung cancer through various mechanisms, including inhibition of cell proliferation, invasion, and metastasis, induction of apoptosis, epigenetic alterations, and regulation of microRNA expression. Several in vitro and in vivo studies have shown that these mechanisms are modulated by multiple molecular targets such as STAT3, EGFR, FOXO3a, TGF-β, eIF2α, COX-2, Bcl-2, PI3KAkt/mTOR, ROS, Fas/FasL, Cdc42, E-cadherin, MMPs, and adiponectin. In addition, limitations, strategies to overcome curcumin bioavailability, and potential side effects as well as clinical trials were also reviewed.
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Affiliation(s)
- Wan Nur Baitty Wan Mohd Tajuddin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; (W.N.B.W.M.T.); (I.O.)
| | - Nordin H. Lajis
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia; (N.H.L.); (F.A.)
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia; (N.H.L.); (F.A.)
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; (W.N.B.W.M.T.); (I.O.)
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; (W.N.B.W.M.T.); (I.O.)
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19
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KRAS Exon 3 and PTEN Exon 7 Mutations in Small-cell Lung Cancer. Curr Med Sci 2019; 39:379-384. [PMID: 31209806 DOI: 10.1007/s11596-019-2046-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 03/26/2019] [Indexed: 12/21/2022]
Abstract
Small cell lung cancer (SCLC) is recognized as one of the most aggressive and fatal malignant tumors. No significant improvement has been made to prolong the survival of SCLC patients. This study aimed to examine the mutation status of K-Ras (KRAS) and phosphatase and tensin homolog (PTEN) in SCLC patients in order to identify potential therapeutic targets for SCLC. Nineteen primary SCLC tumor specimens were enrolled in the study. Direct sequencing was performed to detect the mutations of KRAS exon 3 and PTEN exon 7 in the specimens. Kaplan- Meier and Cox regression analysis was performed to determine the overall survival (OS) of these SCLC patients. KRAS exon 3 mutation was found in 4 (21%) SCLC patients, and PTEN exon 7 mutation in only 1 (5%) SCLC patient. Kaplan Meier analysis showed that clinical stage and brain metastasis were significantly associated with OS (both P<0.05), but neither KRAS exon 3 mutation nor PTEN exon 7 mutation was significantly associated with OS (P>0.05). Cox proportional hazards regression model indicated that extensive stage of disease was the only independent negative prognostic factor for OS in SCLC patients. In conclusion, KRAS exon 3 and PTEN exon 7 mutations had no significant impact on OS of SCLC patients. Further study is still necessary to validate the molecular profiles of SCLC.
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20
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Schulze AB, Evers G, Kerkhoff A, Mohr M, Schliemann C, Berdel WE, Schmidt LH. Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer. Cancers (Basel) 2019; 11:E690. [PMID: 31108964 PMCID: PMC6562929 DOI: 10.3390/cancers11050690] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/29/2019] [Accepted: 05/14/2019] [Indexed: 12/31/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called 'poly-(ADP)-ribose polymerases' (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of 'enhancer of zeste homolog 2' (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future.
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Affiliation(s)
- Arik Bernard Schulze
- Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.
| | - Georg Evers
- Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.
| | - Andrea Kerkhoff
- Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.
| | - Michael Mohr
- Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.
| | - Christoph Schliemann
- Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.
| | - Wolfgang E Berdel
- Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.
| | - Lars Henning Schmidt
- Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.
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21
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Tsoukalas N, Aravantinou-Fatorou E, Baxevanos P, Tolia M, Tsapakidis K, Galanopoulos M, Liontos M, Kyrgias G. Advanced small cell lung cancer (SCLC): new challenges and new expectations. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:145. [PMID: 29862234 DOI: 10.21037/atm.2018.03.31] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Small cell lung cancer (SCLC) remains one of the most lethal malignancies and a major health riddle. The therapeutic options are limited. The combination of etoposide or irinotecan with platinum chemotherapy is the standard of care at any stage. The last decade systemic efforts have been done to reveal specific therapeutic targets for small cell lung carcinomas. In this review, we focus on the new therapeutic strategies of SCLC, including immune-related treatment that may change the prognosis of the disease. The main genetic mutations observed in SCLC are TP53 and RB1 mutations; however, it is well known that these molecules are not yet targetable. In recent years, research has revealed other frequent genetic alterations and activated signaling pathways that might be an effective treatment target. Loss of PTEN, activating PI3K mutations, inhibition of NOTCH pathway and aurora kinase activation are among them. Moreover, FDGFR1 amplification, activation of the Hedgehog pathway and repair-protein PARP1 seem to participate in SCLC tumorigenesis. These new findings have identified some interesting targets. Moreover, immunotherapy tries to find its place in the treatment of SCLC. Immune checkpoint inhibitors are under investigation in phase I to III clinical trials. We hope that in next years the treatment of SCLC patients will be improved with the administration of targeting therapy and the introduction of immunotherapy.
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Affiliation(s)
| | | | | | - Maria Tolia
- Department of Radiotherapy-Radiation Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Konstantinos Tsapakidis
- Department of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | | | - Michail Liontos
- Department of Oncology, Alexandra General Hospital, Athens, Greece
| | - George Kyrgias
- Department of Radiotherapy-Radiation Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
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22
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Ma J, Guo X, Zhang J, Wu D, Hu X, Li J, Lan Q, Liu Y, Dong W. PTEN Gene Induces Cell Invasion and Migration via Regulating AKT/GSK-3β/β-Catenin Signaling Pathway in Human Gastric Cancer. Dig Dis Sci 2017; 62:3415-3425. [PMID: 29030742 DOI: 10.1007/s10620-017-4764-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 09/13/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Abnormality of PTEN gene and Wnt/β-catenin signaling have been strongly implicated in various malignant cancers. Recently, it has been noted that a functional interaction/cross-talk was found between the PTEN/PI3K/AKT and Wnt/β-catenin, which plays a key role in the development of cancers. However, few related studies on gastric cancer are available. AIM We examined the expression of PTEN and β-catenin in gastric cancer tissues and detected whether down-regulation of PTEN promotes the migration and invasion in gastric cancer cells along with its underlying mechanism. MATERIALS AND METHODS Immunocytochemistry, a wound healing assay, a Matrigel invasion assay, an immunofluorescence staining were performed to detect expression of PTEN and β-catenin in gastric cancer and adjacent normal tissues, cell migration, cell invasion, and the effects of PTEN knockdown on β-catenin in cells, respectively. Further, MMP-2 and MMP-9 activities were analyzed by zymography assay. The changes in related proteins were further quantified by western blotting. RESULTS Low expression of PTEN was found in majority of gastric cancer tissues, which showed significant associations with differentiation grade in gastric cancer patients. Further, a negative correlation was revealed between PTEN and β-catenin protein expression in gastric cancer tissues (r = - 0.546, P < 0.01). Additionally, PTEN knockdown promoted the migration and invasion of cells and caused an obvious increase in p-AKT, p-GSK-3β, β-catenin, E-cadherin, MMP-7, MMP-2, and MMP-9 in gastric cancer cells. CONCLUSION Our results indicated PTEN gene might induce cell invasion and migration via regulating AKT/GSK-3β/β-catenin signaling pathway, playing a vital role in the progression of gastric cancer.
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Affiliation(s)
- Jingjing Ma
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People's Republic of China
- Key Laboratory of Hubei Province for Digestive System Disease, Wuhan, Hubei Province, People's Republic of China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - Xufeng Guo
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
- Key Laboratory of Hubei Province for Digestive System Disease, Wuhan, Hubei Province, People's Republic of China
| | - Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People's Republic of China
- Key Laboratory of Hubei Province for Digestive System Disease, Wuhan, Hubei Province, People's Republic of China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - Dandan Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Xue Hu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Jiao Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Qingzhi Lan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Ya Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People's Republic of China.
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23
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Zhang W, Li Y, Wu D. [Advances in the Transformation to Small Cell Lung Cancer from Non-small Cell Lung Cancer Following Acquired Drug-resistance to EGFR Tyrosine Kinase Inhibitors]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2017; 20:720-726. [PMID: 29061221 PMCID: PMC5972996 DOI: 10.3779/j.issn.1009-3419.2017.10.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR TKIs）在治疗携带EGFR基因敏感突变的非小细胞肺癌（non-small cell lung cancer, NSCLC）中已取得显著疗效，但是，耐药的产生几乎是不可避免的，常见的耐药机制包括T790M突变、cMET基因扩增等。目前已有文献报道EGFR-TKI耐药的机制之一为NSCLC转化为小细胞肺癌（small cell lung cancer, SCLC），大约占3%-15%，是一种重要的少见耐药机制，并不为人们所深入了解。本文从“共同起源”和“转化时间节点”两个角度对其进行了归纳总结，重点探讨了其转化的可能机制，目前提出的两种可能转化机制分别为肿瘤异质性假说、NSCLC转化为SCLC假说，还涉及了许多分子水平的改变，如RB1基因缺失、P53基因失活、PTEN M264I基因突变等，同时对该种转化的发病特点、治疗策略等方面进行了归纳与总结。目前仍有许多问题需要进一步研究和解决。
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Affiliation(s)
- Wenqiu Zhang
- Department of Tumor Centre, the First Affiliated Hospital of Jilin University, Changchun 130021, China
| | - Yongqi Li
- Department of Tumor Centre, the First Affiliated Hospital of Jilin University, Changchun 130021, China
| | - Di Wu
- Department of Tumor Centre, the First Affiliated Hospital of Jilin University, Changchun 130021, China
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24
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Abstract
High-grade neuroendocrine carcinomas of the lung are classified into two categories: large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). While typical cases of LCNEC are morphologically distinct from SCLC, the differentiation between LCNEC and SCLC can be challenging in some cases. In fact, there are borderline high-grade neuroendocrine carcinomas that morphologically fall between LCNEC and SCLC. Growing evidence suggests that LCNEC is a histologically and biologically heterogeneous group of tumors. Molecular profiling with next-generation sequencing (NGS) has revealed a few biologically distinct subsets of LCNEC. Of those, the SCLC-like subset is characterized by concurrent inactivating mutations in TP53 and loss of RB1 that are typically seen in SCLC, whereas the non-small cell lung cancer (NSCLC)-like subset frequently harbors molecular alterations that are usually seen in NSCLC. Furthermore, the SCLC-like subset exhibits morphologic features of SCLC, and NSCLC-like morphology predominates in the NSCLC-like subset, although there was a substantial overlap in morphologic features between these subsets. As for the treatment of LCNEC, surgery is advocated for early stage tumors, but surgery alone does not appear to be sufficient and adjuvant chemotherapy, consisting of platinum/etoposide, likely prevents recurrence in patients with completely resected LCNEC. For advanced disease, there have been conflicting reports as to whether LCNEC responds to chemotherapeutic regimens in the similar manner to SCLC rather than NSCLC, and the heterogeneous biology of LCNEC may contribute in part to the discrepant results. A further understanding of the biology of LCNEC will lead to novel approaches to clinical managements of patients with LCNEC.
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Affiliation(s)
- Kenzo Hiroshima
- Department of Pathology, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Sundaresan V, Lin VT, Liang F, Kaye FJ, Kawabata-Iwakawa R, Shiraishi K, Kohno T, Yokota J, Zhou L. Significantly mutated genes and regulatory pathways in SCLC-a meta-analysis. Cancer Genet 2017; 216-217:20-28. [PMID: 29025592 DOI: 10.1016/j.cancergen.2017.05.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 05/06/2017] [Accepted: 05/31/2017] [Indexed: 02/08/2023]
Abstract
Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and demands effective targeted therapeutic strategies. In this meta-analysis study, we aim to identify significantly mutated genes and regulatory pathways to help us better understand the progression of SCLC and to identify potential biomarkers. Besides ranking genes based on their mutation frequencies, we sought to identify statistically significant mutations in SCLC with the MutSigCV software. Our analysis identified several genes with relatively low mutation frequency, including PTEN, as highly significant (p < 0.001), suggesting these genes may play an important role in the progression of SCLC. Our results also indicated mutations in genes involved in the axon guidance pathways likely play an important role in SCLC progression. In addition, we observed that the mutation rate was significantly higher in samples with RB1 gene mutated when compared to samples with wild type RB1, suggesting that RB1 status has significant impact on the mutation profile and disease progression in SCLC.
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Affiliation(s)
- Varsha Sundaresan
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA; UF Health Cancer Center, University of Florida, Gainesville, FL, USA
| | - Victor T Lin
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
| | - Faming Liang
- Department of Biostatistics, University of Florida, Gainesville, FL, USA
| | - Frederic J Kaye
- UF Health Cancer Center, University of Florida, Gainesville, FL, USA; Department of Medicine, University of Florida, Gainesville, FL, USA; UF Genetics Institute, University of Florida, Gainesville, FL, USA
| | - Reika Kawabata-Iwakawa
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo 104-0045, Japan
| | - Jun Yokota
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Cancer Genome Biology Group, Institute of Predictive and Personalized Medicine of Cancer, Barcelona 08916, Spain
| | - Lei Zhou
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA; UF Health Cancer Center, University of Florida, Gainesville, FL, USA; UF Genetics Institute, University of Florida, Gainesville, FL, USA.
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26
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Masunaga A, Omatsu M, Kunimura T, Uematsu S, Kamio Y, Kitami A, Miyagi Y, Hiroshima K, Suzuki T. Expression of PTEN and its pseudogene PTENP1, and promoter methylation of PTEN in non-tumourous thymus and thymic tumours. J Clin Pathol 2017; 70:690-696. [PMID: 28119349 DOI: 10.1136/jclinpath-2016-204220] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 12/27/2016] [Accepted: 12/28/2016] [Indexed: 11/04/2022]
Abstract
AIMS Mutation or promoter methylation of the phosphatase tensin homologue deleted on chromosome 10 tumour suppressor gene (PTEN) promotes some cancers. Moreover, PTENP1 (PTEN pseudogene) transcript regulates PTEN expression and is thought to be associated with tumourigenesis in some cancers. Here, we investigated PTEN expression in thymic epithelium and thymic epithelial tumours. METHODS Immunohistochemical analysis of PTEN was performed on two non-tumourous thymus (NT) samples, 33 thymomas (three type A, eight type AB, 11 type B1, six type B2, and five type B3), and four thymic carcinomas (TCs). In 16 cases (two NT, three A, five B1, two B2, one B3 and three TC), analyses of mutations, promoter methylation and comparisons of PTEN mRNA and PTENP1 transcripts were undertaken using PCR-direct sequencing, methylation-specific PCR, and reverse-transcription real-time PCR after target cell collection with laser microdissection. RESULTS PTEN protein was not immunohistochemically detected in NT epithelium or types B1 or B2 thymoma cells, but was expressed in type A thymoma and carcinoma cells. Neither PTEN mutations nor promoter methylation were detected in any samples. Statistical analysis revealed that PTEN mRNA expression was highest in NT epithelium and lowest in type A thymoma cells. PTENP1 transcript expression did not significantly differ among NT, thymoma and TC samples. CONCLUSIONS We speculated that NT epithelium and types B1/B2 thymoma cells have a mechanism of PTEN translation repression and/or acceleration of protein degradation, whereas type A thymoma cells exhibit transcriptional repression of PTEN mRNA and accelerated translation and/or protein accumulation.
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Affiliation(s)
- Atsuko Masunaga
- Respiratory Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan
| | - Mutsuko Omatsu
- Department of Clinicodiagnostic Pathology, Showa University Northern Yokohama Hospital, Yokohama, Japan
| | - Toshiaki Kunimura
- Department of Clinicodiagnostic Pathology, Showa University Northern Yokohama Hospital, Yokohama, Japan
| | - Shugo Uematsu
- Respiratory Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan
| | - Yoshito Kamio
- Department of Emergency Medicine, Showa University Northern Yokohama Hospital, Yokohama, Japan
| | - Akihiko Kitami
- Respiratory Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan
| | - Yohei Miyagi
- Molecular Pathology & Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Kenzo Hiroshima
- Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan
| | - Takashi Suzuki
- Respiratory Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan
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KH-type splicing regulatory protein (KHSRP) contributes to tumorigenesis by promoting miR-26a maturation in small cell lung cancer. Mol Cell Biochem 2016; 422:61-74. [DOI: 10.1007/s11010-016-2806-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 08/25/2016] [Indexed: 12/17/2022]
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28
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Vijayvergia N, Boland PM, Handorf E, Gustafson KS, Gong Y, Cooper HS, Sheriff F, Astsaturov I, Cohen SJ, Engstrom PF. Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study. Br J Cancer 2016; 115:564-70. [PMID: 27482646 PMCID: PMC4997552 DOI: 10.1038/bjc.2016.229] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 07/01/2016] [Accepted: 07/06/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical. METHODS Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%). RESULTS A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003). CONCLUSIONS Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.
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Affiliation(s)
- Namrata Vijayvergia
- Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA
| | - Patrick M Boland
- Department of Medical Oncology, Roswell Park Cancer Center, Buffalo, NY, USA
| | - Elizabeth Handorf
- Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Karen S Gustafson
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Yulan Gong
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Harry S Cooper
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Fathima Sheriff
- Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA
| | - Igor Astsaturov
- Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA
| | - Steven J Cohen
- Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA
| | - Paul F Engstrom
- Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA
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Ali A, Mehdi SJ, Hajela K, Saluja SS, Mishra PK, Sameer AS, Rizvi MMA. Allelic loss at PTEN locus leads to progression of colorectal carcinoma among North Indian patients. Biomarkers 2016; 21:716-720. [PMID: 27098297 DOI: 10.3109/1354750x.2016.1172115] [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] [Indexed: 11/13/2022]
Abstract
We evaluated the loss of heterozygosity (LOH) at 10q23.3 locus of microsatellite markers; D10S198, D10S192, and D10S541 of PTEN gene in 223 North Indian colorectal cancer (CRC) specimens. DNA was isolated and microsatellite-specific markers polymerase chain reaction was performed. Out of total 223 cases 102 showed LOH for at least one of the locus. In addition, thereto a significant association was found with the clinicopathologic features like grade of differentiation, clinical stage, invasion, lymph node invasion, and the clinical outcome (p < 0.05). These data argue that the given markers to check the possible LOH of PTEN gene at locus 10q23.3 could be considered as one of the diagnostic markers in CRC.
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Affiliation(s)
- Asgar Ali
- a Department of Biochemistry , AIIMS , Patna , India
| | - Syed Jafar Mehdi
- b Department of Biosciences, Genome Biology Lab , Jamia Millia Islamia , New Delhi , India
| | - Krishnan Hajela
- c School of Life Sciences , Devi Ahilya Vishwavidyalaya , Indore , India
| | - Sundeep Singh Saluja
- d Department of Gastrointestinal Surgery , G. B. Pant Hospital , New Delhi , India
| | - Pramod Kumar Mishra
- d Department of Gastrointestinal Surgery , G. B. Pant Hospital , New Delhi , India
| | - Aga Syed Sameer
- e Basic Medical Sciences, College of Medicine-Jeddah, King Saud bin Abdulaziz University for Health Sciences , Riyadh , Saudi Arabia
| | - M Moshahid Alam Rizvi
- b Department of Biosciences, Genome Biology Lab , Jamia Millia Islamia , New Delhi , India
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30
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Tong B, Zhao J, Wang M. [Advances on Driver Mutations of Small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2016; 19:236-40. [PMID: 27118653 PMCID: PMC5999810 DOI: 10.3779/j.issn.1009-3419.2016.04.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
小细胞肺癌是一类具有高度侵袭性的肺恶性肿瘤，预后极差，近30年来，其治疗策略无明显进展。积极研究小细胞肺癌分子生物学特征，并筛选潜在驱动基因，有助于为小细胞肺癌开拓新的治疗途径，改善疾病预后。本文将对小细胞肺癌驱动基因研究相关进展进行综述。
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Affiliation(s)
- Bing Tong
- Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jing Zhao
- Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Mengzhao Wang
- Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
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31
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Bunn PA, Minna JD, Augustyn A, Gazdar AF, Ouadah Y, Krasnow MA, Berns A, Brambilla E, Rekhtman N, Massion PP, Niederst M, Peifer M, Yokota J, Govindan R, Poirier JT, Byers LA, Wynes MW, McFadden DG, MacPherson D, Hann CL, Farago AF, Dive C, Teicher BA, Peacock CD, Johnson JE, Cobb MH, Wendel HG, Spigel D, Sage J, Yang P, Pietanza MC, Krug LM, Heymach J, Ujhazy P, Zhou C, Goto K, Dowlati A, Christensen CL, Park K, Einhorn LH, Edelman MJ, Giaccone G, Gerber DE, Salgia R, Owonikoko T, Malik S, Karachaliou N, Gandara DR, Slotman BJ, Blackhall F, Goss G, Thomas R, Rudin CM, Hirsch FR. Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes? J Thorac Oncol 2016; 11:453-74. [PMID: 26829312 PMCID: PMC4836290 DOI: 10.1016/j.jtho.2016.01.012] [Citation(s) in RCA: 140] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 01/03/2016] [Accepted: 01/05/2016] [Indexed: 12/16/2022]
Affiliation(s)
- Paul A Bunn
- University of Colorado Cancer Center, Aurora, Colorado
| | - John D Minna
- University of Texas Southwestern Medical Center, Dallas, Texas
| | | | - Adi F Gazdar
- University of Texas Southwestern Medical Center, Dallas, Texas
| | | | | | - Anton Berns
- Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | | | | | | | | | - Jun Yokota
- Institute of Predictive and Personalized Medicine of Cancer, Barcelona, Spain; National Cancer Center Research Institute, Tokyo, Japan
| | | | - John T Poirier
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lauren A Byers
- University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Murry W Wynes
- International Association for the Study of Lung Cancer, Aurora, Colorado
| | | | | | | | - Anna F Farago
- Massachusetts General Hospital, Boston, Massachusetts
| | - Caroline Dive
- Cancer Research UK Manchester Institute, Manchester, United Kingdom
| | | | | | - Jane E Johnson
- University of Texas Southwestern Medical Center, Dallas, Texas
| | - Melanie H Cobb
- University of Texas Southwestern Medical Center, Dallas, Texas
| | | | - David Spigel
- Sara Cannon Research Institute, Nashville, Tennessee
| | | | - Ping Yang
- Mayo Clinic Cancer Center, Rochester, Minnesota
| | | | - Lee M Krug
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - John Heymach
- University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Caicun Zhou
- Cancer Institute of Tongji University Medical School, Shanghai, China
| | - Koichi Goto
- National Cancer Center Hospital East, Chiba, Japan
| | - Afshin Dowlati
- Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio
| | | | - Keunchil Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - Martin J Edelman
- University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland
| | | | - David E Gerber
- University of Texas Southwestern Medical Center, Dallas, Texas
| | | | | | | | | | - David R Gandara
- University of California Davis Comprehensive Cancer Center, Davis, California
| | - Ben J Slotman
- Vrije Universiteit Medical Center, Amsterdam, Netherlands
| | | | | | | | | | - Fred R Hirsch
- University of Colorado Cancer Center, Aurora, Colorado.
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Karachaliou N, Pilotto S, Lazzari C, Bria E, de Marinis F, Rosell R. Cellular and molecular biology of small cell lung cancer: an overview. Transl Lung Cancer Res 2016; 5:2-15. [PMID: 26958489 DOI: 10.3978/j.issn.2218-6751.2016.01.02] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although the incidence of small cell lung cancer (SCLC) has declined during the past 30 years, it remains a frustrating disease to research and treat. Numerous attempts to enhance the anti-tumor effects of traditional chemotherapy for SCLC have not been successful. For any tumor to become cancerous, various genetic mutations and biologic alterations must occur in the cell that, when combined, render it a malignant neoplasm. New and novel therapies based on understanding these mechanisms of transformation are needed. Herein we provide an in-depth view of some of the genomic alterations in SCLC that have emerged as potential targets for therapeutic intervention.
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Affiliation(s)
- Niki Karachaliou
- 1 Instituto Oncolόgico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 3 Division of Thoracic Oncology, European Institute of Oncology (IEO), Milan, Italy ; 4 Pangaea Biotech, Barcelona, Spain ; 5 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 6 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain ; 7 Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain
| | - Sara Pilotto
- 1 Instituto Oncolόgico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 3 Division of Thoracic Oncology, European Institute of Oncology (IEO), Milan, Italy ; 4 Pangaea Biotech, Barcelona, Spain ; 5 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 6 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain ; 7 Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain
| | - Chiara Lazzari
- 1 Instituto Oncolόgico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 3 Division of Thoracic Oncology, European Institute of Oncology (IEO), Milan, Italy ; 4 Pangaea Biotech, Barcelona, Spain ; 5 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 6 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain ; 7 Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain
| | - Emilio Bria
- 1 Instituto Oncolόgico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 3 Division of Thoracic Oncology, European Institute of Oncology (IEO), Milan, Italy ; 4 Pangaea Biotech, Barcelona, Spain ; 5 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 6 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain ; 7 Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain
| | - Filippo de Marinis
- 1 Instituto Oncolόgico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 3 Division of Thoracic Oncology, European Institute of Oncology (IEO), Milan, Italy ; 4 Pangaea Biotech, Barcelona, Spain ; 5 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 6 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain ; 7 Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain
| | - Rafael Rosell
- 1 Instituto Oncolόgico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 3 Division of Thoracic Oncology, European Institute of Oncology (IEO), Milan, Italy ; 4 Pangaea Biotech, Barcelona, Spain ; 5 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 6 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain ; 7 Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain
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Koinis F, Kotsakis A, Georgoulias V. Small cell lung cancer (SCLC): no treatment advances in recent years. Transl Lung Cancer Res 2016; 5:39-50. [PMID: 26958492 PMCID: PMC4758968 DOI: 10.3978/j.issn.2218-6751.2016.01.03] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 10/28/2015] [Indexed: 12/23/2022]
Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy with a distinct natural history and dismal prognosis. Given its predisposition for early dissemination, patients are commonly diagnosed with metastatic disease and chemotherapy is regarded as the cornerstone of approved treatment strategies. However, over the last 30 years there has been a distinct paucity of significant breakthroughs in SCLC therapy. Thus, SCLC is characterized as a recalcitrant neoplasm with limited therapeutic options. By employing well-established research approaches, proven to be efficacious in non-small cell lung cancer (NSCLC), a growing amount of data has shed light on the molecular biology of SCLC and enhanced our knowledge of the "drivers" of tumor cell survival and proliferation. New therapeutic targets have emerged, but no significant improvement in patients' survival has been demonstrated thus far. In a sense, the more we know, the more we fail. Nowadays this is starting to change and methodical research efforts are underway. It is anticipated that the next decade will see a revolution in the treatment of SCLC patients with the application of effective precision medicine and immunotherapy strategies.
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Codony-Servat J, Verlicchi A, Rosell R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res 2016; 5:16-25. [PMID: 26958490 PMCID: PMC4758966 DOI: 10.3978/j.issn.2218-6751.2016.01.01] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 10/28/2015] [Indexed: 12/11/2022]
Abstract
Small cell lung cancer (SCLC) is one of the most aggressive lung tumors, with poor survival rates. Although patients may initially respond to treatment, this is followed by rapid development of drug resistance and disease progression. SCLC patients often present with metastasis at time of diagnosis, ruling out surgery as a treatment option. Currently, treatment options for this disease remain limited and platinum-based chemotherapy is the treatment of choice. A better understanding of the biology of SCLC could allow us to identify new therapeutic targets. Cancer stem cell (CSC) theory is currently crucial in cancer research and could provide a viable explanation for the heterogeneity, drug resistance, recurrence and metastasis of several types of tumors. Some characteristics of SCLC, such as aggressiveness, suggest that this kind of tumor could be enriched in CSCs, and drug resistance in SCLC could be attributable to the existence of a CSC subpopulation in SCLC. Herein we summarize current understanding of CSC in SCLC, including the evidence for CSC markers and signaling pathways involved in stemness. We also discuss potential ongoing strategies and areas of active research in SCLC, such as immunotherapy, that focus on inhibition of signaling pathways and targeting molecules driving stemness. Understanding of signaling pathways and the discovery of new therapeutic markers specific to CSCs will lead to new advances in therapy and improvements in prognosis of SCLC patients. Therefore, evaluation of these CSC-specific molecules and pathways may become a routine part of SCLC diagnosis and therapy.
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Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor of the lung with a tendency to metastasize widely early in the course of the disease. The VA staging system classifies the disease into limited stage (LS) which is confined to one hemithorax and can be included into one radiation field or extensive stage (ES) which extends beyond one hemithorax. Current standard of care is concurrent chemoradiation for LS disease and chemotherapy alone for ES disease. Only a quarter of patients with LS disease will be cured with current standard treatments and majority of the patients ultimately succumb to their disease. A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate, however, at the same time this complexity can form the basis for effective targeted therapy for the disease. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors have been unsuccessful in showing a survival advantage in this disease. Several others including DNA repair inhibitors, cellular developmental pathway inhibitors, antibody drug conjugates (ADCs), as well as immune therapy with vaccines, immunomodulators, and immune checkpoint inhibitors are being tested. So far, none of these agents are approved for use in SCLC and the majority are in phase I/II clinical trials, with immune checkpoint inhibitors being the most promising therapeutic strategy. In this article, we will discuss these novel therapeutic agents and currently available data in SCLC.
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Affiliation(s)
- Hirva Mamdani
- 1 Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA ; 2 Levine Cancer Institute, Carolinas HealthCare Systems, Albemarle, NC, USA
| | - Raghava Induru
- 1 Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA ; 2 Levine Cancer Institute, Carolinas HealthCare Systems, Albemarle, NC, USA
| | - Shadia I Jalal
- 1 Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA ; 2 Levine Cancer Institute, Carolinas HealthCare Systems, Albemarle, NC, USA
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Pérez-Ramírez C, Cañadas-Garre M, Molina MÁ, Faus-Dáder MJ, Calleja-Hernández MÁ. PTEN and PI3K/AKT in non-small-cell lung cancer. Pharmacogenomics 2015; 16:1843-62. [DOI: 10.2217/pgs.15.122] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. In the last years, the identification of activating EGFR mutations, conferring increased sensitivity and disease response to tyrosine kinase inhibitors, has changed the prospect of NSCLC patients. The PTEN/PI3K/AKT pathway regulates multiple cellular functions, including cell growth, differentiation, proliferation, survival, motility, invasion and intracellular trafficking. Alterations in this pathway, mainly PTEN inactivation, have been associated with resistance to EGFR-tyrosine kinase inhibitor therapy and lower survival in NSCLC patients. In this review, we will briefly discuss the main PTEN/PI3K/AKT pathway alterations found in NSCLC, as well as the cell processes regulated by PTEN/PI3K/AKT leading to tumorigenesis.
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Affiliation(s)
- Cristina Pérez-Ramírez
- Pharmacogenetics Unit. UGC Provincial de Farmacia de Granada. Instituto de Investigación Biosanitaria de Granada. Complejo Hospitalario Universitario de Granada. Avda. Fuerzas Armadas, 2. 18014 Granada, Spain
- Department of Biochemistry. Faculty of Pharmacy. University of Granada Campus Universitario de Cartuja, s/n. 18071 Granada, Spain
| | - Marisa Cañadas-Garre
- Pharmacogenetics Unit. UGC Provincial de Farmacia de Granada. Instituto de Investigación Biosanitaria de Granada. Complejo Hospitalario Universitario de Granada. Avda. Fuerzas Armadas, 2. 18014 Granada, Spain
| | - Miguel Ángel Molina
- PANGAEA BIOTECH, S.L. Hospital Universitario Quirón Dexeus. C/Sabino Arana, 5-19. 08028 Barcelona
| | - María José Faus-Dáder
- Department of Biochemistry. Faculty of Pharmacy. University of Granada Campus Universitario de Cartuja, s/n. 18071 Granada, Spain
| | - Miguel Ángel Calleja-Hernández
- Pharmacogenetics Unit. UGC Provincial de Farmacia de Granada. Instituto de Investigación Biosanitaria de Granada. Complejo Hospitalario Universitario de Granada. Avda. Fuerzas Armadas, 2. 18014 Granada, Spain
- Department of Pharmacology. Faculty of Pharmacy. University of Granada. Campus Universitario de Cartuja, s/n. 18071 Granada, Spain
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Abstract
Lung cancer is the leading cause of cancer deaths, with small cell lung cancer (SCLC) representing the most aggressive subtype. Standard treatments have not changed in decades, and the 5-year survival rate has remained <7%. Genomic analyses have identified key driver mutations of SCLC that were subsequently validated in animal models of SCLC. To provide better treatment options, a deeper understanding of the cellular and molecular mechanisms underlying SCLC initiation, progression, metastasis, and acquisition of resistance is required. In this review, we describe the genetic landscape of SCLC, features of the cell of origin, and targeted therapeutic approaches.
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Affiliation(s)
- Ekaterina A Semenova
- Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Remco Nagel
- Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Anton Berns
- Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
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Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer. Sci Rep 2015; 5:14447. [PMID: 26400668 PMCID: PMC4585860 DOI: 10.1038/srep14447] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 08/28/2015] [Indexed: 11/09/2022] Open
Abstract
Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.
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George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, Müller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Pützer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmüller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castaños-Vélez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Köhler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansén S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nürnberg P, Reinhardt C, Perner S, Heukamp L, Büttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK. Comprehensive genomic profiles of small cell lung cancer. Nature 2015; 524:47-53. [PMID: 26168399 DOI: 10.1038/nature14664] [Citation(s) in RCA: 1657] [Impact Index Per Article: 165.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 06/15/2015] [Indexed: 02/06/2023]
Abstract
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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Affiliation(s)
- Julie George
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Jing Shan Lim
- Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA
| | - Se Jin Jang
- Department of Pathology and Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea
| | - Yupeng Cun
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Luka Ozretić
- Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany
| | - Gu Kong
- Department of Pathology, College of Medicine, Hanyang University. 222 Wangsimniro, Seongdong-gu, Seoul 133-791, Korea
| | - Frauke Leenders
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Xin Lu
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Lynnette Fernández-Cuesta
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Graziella Bosco
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Christian Müller
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Ilona Dahmen
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Nadine S Jahchan
- Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA
| | - Kwon-Sik Park
- Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA
| | - Dian Yang
- Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA
| | - Anthony N Karnezis
- Vancouver General Hospital, Terry Fox laboratory, Vancouver, British Columbia V5Z 1L3, Canada
| | - Dedeepya Vaka
- Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA
| | - Angela Torres
- Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA
| | - Maia Segura Wang
- European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany
| | - Jan O Korbel
- European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany
| | - Roopika Menon
- Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany
| | - Sung-Min Chun
- Department of Pathology and Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea
| | - Deokhoon Kim
- Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea
| | - Matt Wilkerson
- Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA
| | - Neil Hayes
- UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA
| | - David Engelmann
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany
| | - Brigitte Pützer
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany
| | - Marc Bos
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Sebastian Michels
- Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany
| | - Ignacija Vlasic
- Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany
| | - Danila Seidel
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Berit Pinther
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Philipp Schaub
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Christian Becker
- Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
| | - Janine Altmüller
- 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany
| | - Jun Yokota
- 1] Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. [2] Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona 08916, Spain
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan
| | - Reika Iwakawa
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan
| | - Koji Tsuta
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital Chuo-ku, Tokyo 1040045, Japan
| | - Masayuki Noguchi
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
| | - Thomas Muley
- 1] Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany
| | - Hans Hoffmann
- Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany
| | - Philipp A Schnabel
- 1] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany
| | - Iver Petersen
- Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany
| | - Yuan Chen
- Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany
| | - Alex Soltermann
- Institute of Surgical Pathology, University Hospital Zürich, 8091 Zürich, Switzerland
| | - Verena Tischler
- Institute of Surgical Pathology, University Hospital Zürich, 8091 Zürich, Switzerland
| | - Chang-min Choi
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea
| | - Yong-Hee Kim
- Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea
| | - Pierre P Massion
- Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA
| | - Yong Zou
- Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA
| | - Dragana Jovanovic
- University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade, 11000 Belgrade, Serbia
| | - Milica Kontic
- University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade, 11000 Belgrade, Serbia
| | - Gavin M Wright
- Department of Surgery, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia
| | - Prudence A Russell
- Department of Pathology, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia
| | - Benjamin Solomon
- Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia
| | - Ina Koch
- Asklepios Biobank für Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken München-Gauting 82131, Germany
| | - Michael Lindner
- Asklepios Biobank für Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken München-Gauting 82131, Germany
| | - Lucia A Muscarella
- Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni, Rotondo, Italy
| | - Annamaria la Torre
- Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni, Rotondo, Italy
| | - John K Field
- Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool Cancer Research Centre, 200 London Road, L69 3GA Liverpool, UK
| | - Marko Jakopovic
- University of Zagreb, School of Medicine, Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb, 10000 Zagreb, Croatia
| | - Jelena Knezevic
- Laboratory for Translational Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia
| | | | - Luca Roz
- Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS - Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Ugo Pastorino
- Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Odd-Terje Brustugun
- 1] Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway. [2] Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway
| | - Marius Lund-Iversen
- Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway
| | - Erik Thunnissen
- Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Jens Köhler
- 1] West German Cancer Center, Department of Medical Oncology, University Hospital Essen, 45147 Essen, Germany. [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Martin Schuler
- 1] West German Cancer Center, Department of Medical Oncology, University Hospital Essen, 45147 Essen, Germany. [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Johan Botling
- Departments of Immunology, Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, 75185 Uppsala, Sweden
| | - Martin Sandelin
- Departments of Immunology, Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, 75185 Uppsala, Sweden
| | - Montserrat Sanchez-Cespedes
- Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain
| | - Helga B Salvesen
- 1] Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, N-5058 Bergen, Norway. [2] Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5058 Bergen, Norway
| | - Viktor Achter
- Computing Center, University of Cologne, 50931 Cologne, Germany
| | - Ulrich Lang
- 1] Computing Center, University of Cologne, 50931 Cologne, Germany. [2] Department of Informatics, University of Cologne, 50931 Cologne, Germany
| | - Magdalena Bogus
- Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany
| | - Peter M Schneider
- Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany
| | - Thomas Zander
- Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne-Bonn, Department I for Internal Medicine, University Hospital of Cologne, 50937 Cologne, Germany
| | - Sascha Ansén
- Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany
| | - Michael Hallek
- 1] Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Jürgen Wolf
- Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany
| | - Martin Vingron
- Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 464-8681 Nagoya, Japan
| | - William D Travis
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Peter Nürnberg
- 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. [3] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Christian Reinhardt
- Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany
| | - Sven Perner
- Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea
| | - Lukas Heukamp
- Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany
| | - Reinhard Büttner
- Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany
| | - Stefan A Haas
- Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
| | - Elisabeth Brambilla
- Department of Pathology, CHU Grenoble INSERM U823, University Joseph Fourier, Institute Albert Bonniot 38043, CS10217 Grenoble, France
| | - Martin Peifer
- 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Julien Sage
- Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA
| | - Roman K Thomas
- 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany
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40
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Arcaro A. Targeted therapies for small cell lung cancer: Where do we stand? Crit Rev Oncol Hematol 2015; 95:154-64. [PMID: 25800975 DOI: 10.1016/j.critrevonc.2015.03.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 01/23/2015] [Accepted: 03/04/2015] [Indexed: 12/19/2022] Open
Abstract
Small cell lung cancer (SCLC) accounts for 15% of lung cancer cases and is associated with a dismal prognosis. Standard therapeutic regimens have been improved over the past decades, but without a major impact on patient survival. The development of targeted therapies based on a better understanding of the molecular basis of the disease is urgently needed. At the genetic level, SCLC appears very heterogenous, although somatic mutations targeting classical oncogenes and tumor suppressors have been reported. SCLC also possesses somatic mutations in many other cancer genes, including transcription factors, enzymes involved in chromatin modification, receptor tyrosine kinases and their downstream signaling components. Several avenues have been explored to develop targeted therapies for SCLC. So far, however, there has been limited success with these targeted approaches in clinical trials. Further progress in the optimization of targeted therapies for SCLC will require the development of more personalized approaches for the patients.
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Affiliation(s)
- Alexandre Arcaro
- Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
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41
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Milella M, Falcone I, Conciatori F, Cesta Incani U, Del Curatolo A, Inzerilli N, Nuzzo CMA, Vaccaro V, Vari S, Cognetti F, Ciuffreda L. PTEN: Multiple Functions in Human Malignant Tumors. Front Oncol 2015; 5:24. [PMID: 25763354 PMCID: PMC4329810 DOI: 10.3389/fonc.2015.00024] [Citation(s) in RCA: 349] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 01/22/2015] [Indexed: 12/16/2022] Open
Abstract
PTEN is the most important negative regulator of the PI3K signaling pathway. In addition to its canonical, PI3K inhibition-dependent functions, PTEN can also function as a tumor suppressor in a PI3K-independent manner. Indeed, the PTEN network regulates a broad spectrum of biological functions, modulating the flow of information from membrane-bound growth factor receptors to nuclear transcription factors, occurring in concert with other tumor suppressors and oncogenic signaling pathways. PTEN acts through its lipid and protein phosphatase activity and other non-enzymatic mechanisms. Studies conducted over the past 10 years have expanded our understanding of the biological role of PTEN, showing that in addition to its ability to regulate proliferation and cell survival, it also plays an intriguing role in regulating genomic stability, cell migration, stem cell self-renewal, and tumor microenvironment. Changes in PTEN protein levels, location, and enzymatic activity through various molecular mechanisms can generate a continuum of functional PTEN levels in inherited syndromes, sporadic cancers, and other diseases. PTEN activity can indeed, be modulated by mutations, epigenetic silencing, transcriptional repression, aberrant protein localization, and post-translational modifications. This review will discuss our current understanding of the biological role of PTEN, how PTEN expression and activity are regulated, and the consequences of PTEN dysregulation in human malignant tumors.
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Affiliation(s)
- Michele Milella
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Italia Falcone
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Fabiana Conciatori
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Ursula Cesta Incani
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Anais Del Curatolo
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Nicola Inzerilli
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Carmen M A Nuzzo
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Vanja Vaccaro
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Sabrina Vari
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Francesco Cognetti
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
| | - Ludovica Ciuffreda
- Division of Medical Oncology A, Regina Elena National Cancer Institute , Rome , Italy
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Zheng X, Liu D, Fallon JT, Zhong M. Distinct genetic alterations in small cell carcinoma from different anatomic sites. Exp Hematol Oncol 2015; 4:2. [PMID: 25937998 PMCID: PMC4417281 DOI: 10.1186/2162-3619-4-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 01/02/2015] [Indexed: 12/11/2022] Open
Abstract
Small cell carcinoma (SmCC) is a distinct clinicopathological entity first described in the lung. It represents approximately 15% of all bronchogenic carcinoma. Extrapulmonary small cell carcinoma (EPSmCC) morphologically indistinguishable from small cell lung cancer (SCLC) was first reported in 1930. Since its first description, EPSmCC has been reported in virtually all anatomical sites, including: gynecologic organs (ovary and cervix); genitourinary organs (urinary bladder and prostate); the gastrointestinal tract (esophagus); skin (Merkel cell carcinoma) and head and neck region. Regardless of the anatomic sites, all SmCCs have similar, if not identical, histo-pathology features and immunohistochemical profile. SmCC is one of the most aggressive malignancies. The molecular mechanisms underlying its development and progression remain poorly understood. Herein, we reviewed the literature in SmCC in respect to its site of occurrence, clinical features, immunohistochemical characteristics. SmCCs have heterogeneous molecular mutations. Dinstinct genetic alterations associated with SmCC from different body sites were reviewed. Some genetic alterations such as RB1, TP53 are commonly seen in different origins of SmCC. Other genes with site specificity were also summarized, such as bladder SmCC with TERT promoter mutations; prostate SmCC with ERG translocations; ovarian SmCC with SMARCA4 mutations; Merkel cell carcinoma (skin) and cervical SmCC with Merkel cell polyomavirus (MCV or MCPyV) and human papillomavirus (HPV). Further studies are needed to employ a genetically oriented approach for the diagnosis and therapy of SmCC.
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Affiliation(s)
- Xiaoyong Zheng
- Department of Pathology, Westchester Medical Center/New York Medical College, Valhalla, NY USA
| | - Delong Liu
- Henan Tumor Hospital, Zhengzhou University, Zhengzhou, China
| | - John T Fallon
- Department of Pathology, Westchester Medical Center/New York Medical College, Valhalla, NY USA
| | - Minghao Zhong
- Department of Pathology, Westchester Medical Center/New York Medical College, Valhalla, NY USA
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Sun Z, Wang Z, Liu X, Wang D. New development of inhibitors targeting the PI3K/AKT/mTOR pathway in personalized treatment of non-small-cell lung cancer. Anticancer Drugs 2015; 26:1-14. [PMID: 25304988 DOI: 10.1097/cad.0000000000000172] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) is the most common pathological type of lung cancer, divided into squamous cell carcinoma and adenocarcinoma. Despite better techniques of surgery and improvement in adjuvant and neoadjuvant therapy, the median survival of advanced NSCLC is only 8-10 months. With increased understanding of molecular alternations in NSCLC, considerable efforts have focused on the development of personalized molecular-targeted therapies. The PI3K/AKT/mTOR pathway regulates tumor development, growth, and proliferation of NSCLC. Various novel inhibitors targeting this pathway have been identified in preclinical studies or clinical trials. Some genetic alternations may be considered sensitive or resistant biomarkers to these inhibitors. Sometimes, upregulation of RTK and the downstream PI3K pathway or upregulation of the ERK pathway by compensatory feedback reactivation in response to these inhibitors also lead to drug resistance. Therefore, combination therapy of these inhibitors and other targeted inhibitors such as EGFR-TKI or MEK inhibitors according to genetic status and categories of inhibitors is required to enhance the efficacy of these inhibitors. Here, we reviewed the genetic status of the PI3K/AKT/mTOR pathway in NSCLC and the novel inhibitors targeting this pathway in preclinical or clinical studies, exploring the possible genetic alternations related to different inhibitors and the means to enhance the antitumor effect in NSCLC.
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Affiliation(s)
- Zhenguo Sun
- Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, China
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Liu Z, Ke F, Duan C, Lan H, Li J, Gao C, Li J, Zhong Z. Mannan-conjugated adenovirus enhanced gene therapy effects on murine hepatocellular carcinoma cells in vitro and in vivo. Bioconjug Chem 2014; 24:1387-97. [PMID: 23937094 DOI: 10.1021/bc400215a] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The incidence of advanced hepatocellular carcinoma (HCC) is increasing worldwide, and its prognosis is extremely poor. For some patients for whom surgical treatments are not appropriate, one can only rely on chemotherapy. In the conventional chemotherapy, side effects usually occurred in most cases due to high toxicity levels. Moreover, the development of drug resistance toward chemotherapeutic agents often prevents the successful long-term use of chemotherapy for HCC. Gene therapy represents the exciting biotechnological advance that may revolutionize the conventional fashion of cancer treatment. Overexpression of phosphatase and tensin homologue (PTEN) in cancer cells carrying deletion/mutant type of it can induce the apoptosis of cancer cells and inhibit cell proliferation. In this work, in order to make full use of the high transfectivity of adenovirus, we managed to conjugate the polysaccharide mannan (polymannose) to the surface of the adenovirus chemically under appropriate oxidizing conditions to prepare the mannan-modified adenovirus (Man-Ad5-PTEN). The cytotoxicity and anticancer activity of Man-Ad5-PTEN were assessed in vitro. Reporter gene expression of LacZ transferred by Man-Ad5-LacZ was verified on mannose receptor-deficient NIH/3T3 cells versus mannose receptor-efficient macrophages. Hepatocellular carcinoma cell lines transduced by mannan-modified adenovirus were assayed for cell cycle, apoptosis, invasion, and migration. Further, we detected the antitumor effect on intraperitoneal H22 tumor-bearing mice treated by Man-Ad5-PTEN alone or combined with chemotherapeutic agent of doxorubicin. The results demonstrated that cell growth suppression was not observed in Chang normal hepatocyte cells and the cell killing by Man-Ad5-PTEN is tumor selective. Further, the results showed that the strategy of mannan conjugation could enhance adenovirus-mediated PTEN gene therapy effects on murine hepatocellular carcinoma cells in vitro and in vivo.
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Gelsomino F, Rossi G, Tiseo M. MET and Small-Cell Lung Cancer. Cancers (Basel) 2014; 6:2100-15. [PMID: 25314153 PMCID: PMC4276958 DOI: 10.3390/cancers6042100] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 09/21/2014] [Accepted: 09/22/2014] [Indexed: 01/21/2023] Open
Abstract
Small-cell lung cancer (SCLC) is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC.
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Affiliation(s)
- Francesco Gelsomino
- Medical Oncology Unit 1, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano, Italy.
| | - Giulio Rossi
- Operative Unit of Pathology, Azienda Ospedaliero-Universitaria Policlinico, Via del Pozzo 71, 41124 Modena, Italy.
| | - Marcello Tiseo
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Viale A. Gramsci 14, 43126 Parma, Italy.
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McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, Stewart C, Carter SL, Cibulskis K, Bhutkar A, McKenna A, Dooley A, Vernon A, Sougnez C, Malstrom S, Heimann M, Park J, Chen F, Farago AF, Dayton T, Shefler E, Gabriel S, Getz G, Jacks T. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 2014; 156:1298-1311. [PMID: 24630729 DOI: 10.1016/j.cell.2014.02.031] [Citation(s) in RCA: 232] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2013] [Revised: 11/27/2013] [Accepted: 02/12/2014] [Indexed: 12/14/2022]
Abstract
Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs.
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Affiliation(s)
- David G McFadden
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Thales Papagiannakopoulos
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Amaro Taylor-Weiner
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Chip Stewart
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Scott L Carter
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Kristian Cibulskis
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Arjun Bhutkar
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Aaron McKenna
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Alison Dooley
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Amanda Vernon
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Carrie Sougnez
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Scott Malstrom
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Megan Heimann
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Jennifer Park
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Frances Chen
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Anna F Farago
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Talya Dayton
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Erica Shefler
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Stacey Gabriel
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Gad Getz
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
| | - Tyler Jacks
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
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CARNEIRO JULIANAG, COUTO PATRICIAG, BASTOS-RODRIGUES LUCIANA, BICALHO MARIAAPARECIDAC, VIDIGAL PAULAV, VILHENA ALYNE, AMARAL NILSONF, BALE ALLENE, FRIEDMAN EITAN, DE MARCO LUIZ. Spectrum of somatic EGFR, KRAS, BRAF, PTEN mutations and TTF-1 expression in Brazilian lung cancer patients. Genet Res (Camb) 2014; 96:e002. [PMID: 24594201 PMCID: PMC7045132 DOI: 10.1017/s0016672314000032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 12/27/2013] [Accepted: 01/07/2013] [Indexed: 12/19/2022] Open
Abstract
Lung cancer is the leading global cause of cancer-related mortality. Inter-individual variability in treatment response and prognosis has been associated with genetic polymorphisms in specific genes: EGFR, KRAS, BRAF, PTEN and TTF-1. Somatic mutations in EGFR and KRAS genes are reported at rates of 15-40% in non-small cell lung cancer (NSCLC) in ethnically diverse populations. BRAF and PTEN are commonly mutated genes in various cancer types, including NSCLC, with PTEN mutations exerting an effect on the therapeutic response of EGFR/AKT/PI3K pathway inhibitors. TTF-1 is expressed in approximately 80% of lung adenocarcinomas and its positivity correlates with higher prevalence of EGFR mutation in this cancer type. To determine molecular markers for lung cancer in Brazilian patients, the rate of the predominant EGFR, KRAS, BRAF and PTEN mutations, as well as TTF-1 expression, was assessed in 88 Brazilian NSCLC patients. EGFR exon 19 deletions (del746-750) were detected in 3/88 (3·4%) patients. Activating KRAS mutations in codons 12 and 61 were noted in five (5·7%) and two (2·3%) patients, respectively. None of the common somatic mutations were detected in either the BRAF or PTEN genes. TTF-1 was overexpressed in 40·7% of squamous-cell carcinoma (SCC). Our findings add to a growing body of data that highlights the genetic heterogeneity of the abnormal EGFR pathway in lung cancer among ethnically diverse populations.
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Affiliation(s)
- JULIANA G. CARNEIRO
- Faculdade de Ciências Médicas, Centro de Ensino Superior e Desenvolvimento, Campina Grande, 58411-020, Brasil
- Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brasil
| | - PATRICIA G. COUTO
- Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brasil
| | | | | | - PAULA V. VIDIGAL
- Department of Pathology, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brasil
| | - ALYNE VILHENA
- Hospital Julia Kubitscheck, Belo Horizonte, 30620-470, Brasil
| | | | - ALLEN E. BALE
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA
| | - EITAN FRIEDMAN
- The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel
| | - LUIZ DE MARCO
- Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brasil
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Identification and validation of PROM1 and CRTC2 mutations in lung cancer patients. Mol Cancer 2014; 13:19. [PMID: 24484648 PMCID: PMC4062918 DOI: 10.1186/1476-4598-13-19] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 01/21/2014] [Indexed: 02/05/2023] Open
Abstract
Background Genetic alterations could be responsible lung cancer, the leading cause of worldwide cancer death. Methods This study investigated gene mutations in a Han Chinese family of lung cancer using the whole genome exome sequencing and subsequent Sanger sequencing validation and then confirmed alteration of prominin 1(PROM1) and cyclic AMP-response element binding protein-regulated transcription co-activator2 (CRTC2) in blood samples of 343 sporadic lung cancer patients vs. 280 healthy controls as well as in 200 pairs of lung cancer and the corresponding normal tissues using PCR-restriction fragment length polymorphism and directed DNA sequencing of PCR products. Results The data showed PROM1 (p. S281R) and CRTC2 (p. R379C) mutations, in 5 and 2 cases of these 343 sporadic lung cancer patients, respectively. Notably, these mutations were absent in the healthy controls. Furthermore, in the 200 lung cancer and the matched normal tissues, PROM1 mutation occurred in 3 patients (i.e., one squamous cell carcinoma and two adenocarcinomas) with a mutation frequency of 1.5%, while CRTC2 mutation occurred in 5 patients (two squamous cell carcinomas and three adenocarcinomas) with a mutation frequency of 2.5%. Conclusions The data from the current study demonstrated novel PROM1 and CRTC2 mutations, which could promote lung cancer development.
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Cui M, Augert A, Rongione M, Conkrite K, Parazzoli S, Nikitin AY, Ingolia N, MacPherson D. PTEN is a potent suppressor of small cell lung cancer. Mol Cancer Res 2014; 12:654-9. [PMID: 24482365 DOI: 10.1158/1541-7786.mcr-13-0554] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
UNLABELLED Small cell lung carcinoma (SCLC) is a highly metastatic tumor type with neuroendocrine features and a dismal prognosis. PTEN mutations and PIK3CA activating mutations have been reported in SCLC but the functional relevance of this pathway is unknown. The PTEN/PIK3CA pathway was interrogated using an AdenoCre-driven mouse model of SCLC harboring inactivated Rb and p53. Inactivation of one allele of PTEN in Rb/p53-deleted mice led to accelerated SCLC with frequent metastasis to the liver. In contrast with the high mutation burden reported in human SCLC, exome analyses revealed a low number of protein-altering mutations in mouse SCLC. Inactivation of both alleles of PTEN in the Rb/p53-deleted system led to nonmetastatic adenocarcinoma with neuroendocrine differentiation. This study reveals a critical role for the PTEN/PI3K pathway in both SCLC and lung adenocarcinoma and provides an ideal system to test the phosphoinositide 3-kinase (PI3K) pathway inhibitors as targeted therapy for subsets of patients with SCLC. IMPLICATIONS The ability of PTEN inactivation to accelerate SCLC in a genetic mouse model suggests that targeting the PTEN pathway is a therapeutic option for a subset of human patients with SCLC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/28/1541-7786.MCR-13-0554/F1.large.jpg.
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Affiliation(s)
- Min Cui
- Authors' Affiliations: Department of Embryology, Carnegie Institution, Baltimore, Maryland; 2Fred Hutchinson Cancer Research Center, Seattle, Washington; and 3Department of Biomedical Sciences, Cornell University, Ithaca, New York
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Abstract
This article presents an overview of the PI3K/Akt/mTOR signaling pathway. As a central regulator of cell growth, protein translation, survival, and metabolism, activation of this signaling pathway contributes to the pathogenesis of many tumor types. Biochemical and genetic aberrations of this pathway observed in various cancer types are explored. Last, pathway inhibitors both in development and already approved by the Food and Drug Administration are discussed.
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